Spirocyclic cyclohexane compounds

ABSTRACT

Spirocyclic cyclohexane compounds corresponding to formula I 
                         
a method for producing them, pharmaceutical compositions containing them, and methods of using them.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 12/372,358,filed Feb. 17, 2009, now U.S. Pat. No. 7,799,931, which was a divisionof application Ser. No. 11/126,139, filed May 11, 2005, now U.S. Pat.No. 7,547,707, which in turn was a continuation of international patentapplication no. PCT/EP2003/012305, filed Nov. 5, 2003 designating theUnited States of America, and published in German on May 27, 2004 as WO2004/043967, the entire disclosure of which is incorporated herein byreference. Priority is claimed based on Federal Republic of Germanypatent application no. DE 102 52 667.2, filed Nov. 11, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to spirocyclic cyclohexane derivatives,processes for their preparation, medicaments comprising these compoundsand the use of spirocyclic cyclohexane derivatives for the preparationof medicaments.

The heptadecapeptide nociceptin is an endogenous ligand of the ORL1(opioid receptor-like) receptor (Meunier et al., Nature 377, 1995, p.532-535), which belongs to the family of opioid receptors and is to befound in many regions of the brain and spinal cord, and has a highaffinity for the ORL1 receptor. The ORL1 receptor is homologous to theμ, κ and δ opioid receptors and the amino acid sequence of thenociceptin peptide has a marked similarity to those of the known opioidpeptides. The receptor activation induced by nociceptin leads, viacoupling with G_(i/o) proteins, to an inhibition of adenylate cyclase(Meunier et al., Nature 377, 1995, p. 532-535).

The nociceptin peptide shows a pronociceptive and hyperalgesic activityafter intercerebroventicular administration in various animal models(Reinscheid et al., Science 270, 1995, p. 792-794). These findings canbe explained as an inhibition of stress-induced analgesia (Mogil et al.,Neuroscience 75, 1996, p. 333-337). In this connection, it has also beenpossible to demonstrate an anxiolytic activity of nociceptin (Jenck etal., Proc. Natl. Acad. Sci. USA 94, 1997, 14854-14858).

On the other hand, it has also been possible to demonstrate anantinociceptive effect of nociceptin in various animal models, inparticular after intrathecal administration. Nociceptin has anantinociceptive action in various pain models, for example in the tailflick test in the mouse (King et al., Neurosci. Lett., 223, 1997,113-116. It has likewise been possible to demonstrate an antinociceptiveaction of nociceptin in models for neuropathic pain, which is ofparticular interest inasmuch as the activity of nociceptin increasesafter axotomy of spinal nerves. This is in contrast to conventionalopioids, the activity of which decreases under these conditions (Abdullaand Smith, J. Neurosci., 18, 1998, p. 9685-9694).

The ORL1 receptor is moreover also involved in regulation of furtherphysiological and pathophysiological processes. These include, interalia, learning and memory development (Manabe et al., Nature, 394, 1997,p. 577-581), audition (Nishi et al., EMBO J., 16, 1997, p. 1858-1864)and numerous further processes. A review article by Calo et al. (Br. J.Pharmacol., 129, 2000, 1261-1283) gives an overview of the indicationsor biological processes in which the ORL1 receptor plays a role or withhigh probability could play a role. This mentions, inter alia:analgesia, stimulation and regulation of food intake, influence onμ-agonists, such as morphine, treatment of withdrawal symptoms,reduction in the addiction potential of opioids, anxiolysis, modulationof motor activity, impaired memory, epilepsy; modulation ofneurotransmitter secretion, in particular glutamate, serotonin anddopamine, and therefore neurodegenerative diseases; influencing of thecardiovascular system, initiation of an erection, diuresis,anti-natriuresis, electrolyte balance, arterial blood pressure, waterretention diseases, intestinal motility (diarrhea), relaxing effects onthe respiratory tract, micturation reflex (urinary incontinence). Theuse of agonists and antagonists as anoretics, analgesics (also inco-administration with opioids) or nootropics is furthermore discussed.

The possible uses of compounds which bind to the ORL1 receptor andactivate or inhibit this are correspondingly diverse. Alongside this,however, opioid receptors, such as the μ-receptor, but also the othersub-types of these opioid receptors, namely δ and κ, play a large roleprecisely in the area of pain therapy, but also in that of otherindications of those mentioned. Accordingly, it is favourable if thecompound also show an action on these opioid receptors.

SUMMARY OF THE INVENTION

The object of the present invention was to provide medicaments which acton the nociceptin/ORL1 receptor system and are therefore suitable formedicaments, in particular for treatment of the various diseasesassociated, according to the prior art, with this system and for use inthe indications mentioned there.

The invention therefore provides spirocyclic cyclohexane derivatives ofthe general formula I

wherein

-   R¹ and R² independently of one another represent H; CHO; C₁₋₅-alkyl    in each case saturated or unsaturated, branched or unbranched, mono-    or polysubstituted or unsubstituted; C₃₋₈-cycloalkyl, in each case    saturated or unsaturated, mono- or polysubstituted or unsubstituted;    or aryl, C₃₋₈-cycloalkyl or heteroaryl which are bonded via    C₁₋₃-alkyl and are in each case mono- or polysubstituted or    unsubstituted; or-   R¹ and R² together represent CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹¹CH₂CH₂ or    (CH₂)₃₋₆    -   wherein    -   R¹¹ denotes H; C₁₋₅-alkyl, in each case saturated or        unsaturated, branched or unbranched, mono- or polysubstituted or        unsubstituted; C₃₋₈-cycloalkyl, in each case saturated or        unsaturated, mono- or polysubstituted or unsubstituted; aryl-,        or heteroaryl, in each case mono- or polysubstituted or        unsubstituted; or aryl, C₃₋₈-cycloalkyl or heteroaryl which are        bonded via C₁₋₃-alkyl and are in each case mono- or        polysubstituted or unsubstituted;-   R³ represents C₁₋₅-alkyl, in each case saturated or unsaturated,    branched or unbranched, mono- or polysubstituted or unsubstituted;    C₃₋₈-cycloalkyl, in each case saturated or unsaturated, mono- or    polysubstituted or unsubstituted; aryl, in each case unsubstituted    or mono- or polysubstituted; aryl or C₃₋₈-cycloalkyl which are    bonded via C₁₋₃-alkyl group and are in each case unsubstituted or    mono- or polysubstituted;-   W represents NR⁴, O or S    -   wherein    -   R⁴ represents H; C₁₋₅-alkyl, saturated or unsaturated, branched        or unbranched, unsubstituted or mono- or polysubstituted; aryl,        or heteroaryl, in each case substituted or unsubstituted; aryl,        heteroaryl or cycloalkyl which are bonded via a C₁₋₃-alkyl group        and are in each case mono- or polysubstituted or unsubstituted;        COR¹²; SO₂R¹²,        -   wherein        -   R¹² denotes H; C₁₋₅-alkyl, in each case saturated or            unsaturated, branched or unbranched, mono- or            polysubstituted or unsubstituted; C₃₋₈-cycloalkyl, in each            case saturated or unsaturated, mono- or polysubstituted or            unsubstituted; aryl-, or heteroaryl, in each case mono- or            polysubstituted or unsubstituted; or aryl, C₃₋₈-cycloalkyl            or heteroaryl which are bonded via C₁₋₃-alkyl and are in            each case mono- or polysubstituted or unsubstituted; OR¹³;            NR¹⁴R¹⁵;-   R⁵ represents ═O; H; C₁₋₅-alkyl, saturated or unsaturated, branched    or unbranched, unsubstituted or mono- or polysubstituted; COOR¹³,    CONR¹³, OR¹³; C₃₋₈-cycloalkyl, saturated or unsaturated,    unsubstituted or mono- or polysubstituted; aryl-, or heteroaryl,    unsubstituted or mono- or polysubstituted; or aryl, C₃₋₈-cycloalkyl    or heteroaryl which are bonded C₁₋₃-alkyl and are unsubstituted or    mono- or polysubstituted;-   R⁶ represents H; F, Cl, NO₂, CF₃, OR¹³, SR¹³, SO₂R¹³, SO₂OR¹³, CN,    COOR¹³, NR¹⁴R¹⁵; C₁₋₅-alkyl, saturated or unsaturated, branched or    unbranched, unsubstituted or mono- or polysubstituted;    C₃₋₈-cycloalkyl, saturated or unsaturated, unsubstituted or mono- or    polysubstituted; aryl-, or heteroaryl, unsubstituted or mono- or    polysubstituted; or aryl, C₃₋₈-cycloalkyl or heteroaryl which are    bonded via C₁₋₃-alkyl and are unsubstituted or mono- or    polysubstituted; or-   R⁵ and R⁶ together denote (CH₂)_(n), where n=2, 3, 4, 5 or 6,    wherein individual hydrogen atoms can also be replaced by F, Cl, Br,    I, NO₂, CF₃, OR¹³, CN or C₁₋₅-alkyl;-   R⁷, R⁸, R⁹ and R¹⁰ independently of one another represent H, F, Cl,    Br, I, NO₂, CF³, OR¹³, SR¹³, SO₂R¹³, SO₂OR¹³, SO₂NH₂, CN, COOR¹³,    NR¹⁴R¹⁵; C₁₋₅-alkyl, C₃₋₈-cycloalkyl, unsubstituted or mono- or    polysubstituted; aryl-, or heteroaryl, unsubstituted or mono- or    polysubstituted; or aryl, C₃₋₈-cycloalkyl or heteroaryl which are    bonded via C₁₋₃-alkyl and are unsubstituted or mono- or    polysubstituted;    -   wherein    -   R¹³ denotes H; C₁₋₅-alkyl in each case saturated or unsaturated,        branched or unbranched, unsubstituted or mono- or        polysubstituted; C₃₋₈-cycloalkyl, in each case saturated or        unsaturated, unsubstituted or mono- or polysubstituted; aryl-,        or heteroaryl, unsubstituted or mono- or polysubstituted; or        aryl, C₃₋₈-cycloalkyl or heteroaryl which are bonded via        C₁₋₃-alkyl and are unsubstituted or mono- or polysubstituted;    -   R¹⁴ and R¹⁵ independently of one another denote H; C₁₋₅-alkyl,        in each case saturated or unsaturated, branched or unbranched,        unsubstituted or mono- or polysubstituted; or C₃₋₈-cycloalkyl,        in each case saturated or unsaturated, unsubstituted or mono- or        polysubstituted; aryl-, or heteroaryl, unsubstituted or mono- or        polysubstituted; or aryl, C₃₋₈-cycloalkyl or heteroaryl which        are bonded via C₁₋₃-alkyl and are unsubstituted or mono- or        polysubstituted; or    -   R¹⁴ and R¹⁵ together form CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁶CH₂CH₂ or        (CH₂)₃₋₆,        -   wherein        -   R¹⁶ denotes H; C₁₋₅-alkyl saturated or unsaturated, branched            or unbranched, unsubstituted or mono- or polysubstituted;-   X represents O, S, SO, SO₂ or NR¹⁷;    -   wherein    -   R¹⁷ denotes H; C₁₋₅-alkyl, saturated or unsaturated, branched or        unbranched; COR¹² or SO₂R¹²,        in the form of the racemate; the enantiomers, diastereomers,        mixtures of the enantiomers or diastereomers or an individual        enantiomer or diastereomer; or the bases and/or salts of        physiologically acceptable acids or cations.

Where various radicals are combined, for example R⁷, R⁸, R⁹ and R¹⁰, andradicals on substituents thereof are combined, such as e.g. OR¹³, SR¹³,SO2R¹³ or COOR¹³, one substituent, e.g. R¹³, can assume differentmeanings for two or more radicals, for example R⁷, R⁸, R⁹ and R¹⁰,within a substance.

The compounds according to the invention show good binding to the ORL1receptor, but also to other opioid receptors.

In the context of this invention, the expressions “C₁₋₅-alkyl” and“C₁₋₃-alkyl” include acyclic saturated or unsaturated hydrocarbonradicals, which can be branched- or straight-chain and unsubstituted ormono- or polysubstituted, having 1, 2, 3, 4 or 5 C atoms or,respectively, 1, 2 or 3 C atoms, i.e. C₁₋₅-alkanyls, C₂₋₅-alkenyls andC₂₋₅-alkynyls or, respectively, C₁₋₃-alkanyls, C₂₋₃-alkenyls andC₂₋₃-alkynyls. Alkenyls here have at least one C—C double bond andalkynyls at least one C—C triple bond. Alkyl is advantageously chosenfrom the group which includes methyl, ethyl, n-propyl, 2-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl,neo-pentyl, n-hexyl, 2-hexyl; ethylenyl(vinyl), ethynyl, propenyl(—CH₂CH═CH₂, —CH═CH—CH₃, —C(═CH₂)—CH₃), propynyl (—CH—C≡CH, —C≡C—CH₃),1,1-dimethylethyl, 1,1-dimethylpropyl, butenyl, butynyl, pentenyl andpentynyl.

For the purposes of this invention, the expression “cycloalkyl” or“C₃₋₈-cycloalkyl” means cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8carbon atoms, wherein the hydrocarbons can be saturated or unsaturated(but not aromatic), unsubstituted or mono- or polysubstituted. Withreference to cycloalkyl, the term also includes saturated or unsaturated(but not aromatic) cycloalkyls in which one or two carbon atoms arereplaced by a heteroatom S, N or O. C₃₋₈-Cycloalkyl is advantageouslychosen from the group which contains cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl,cyclohexenyl, cycloheptenyl and cyclooctenyl, but alsotetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl,piperazinyl, pyrazolinonyl and pyrrolidinyl.

The term (CH₂)₃₋₆ is to be understood as meaning —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—.

In the context of this invention, the expression “aryl” meanscarbocyclic ring systems having at least one aromatic ring, but withoutheteroatoms in only one of the rings, inter alia phenyls, naphthyls andphenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.The aryl radicals can also be fused with further saturated, (partly)unsaturated or aromatic ring systems. Each aryl radical can beunsubstituted or mono- or polysubstituted, wherein the substituents onthe aryl can be identical or different and in any desired and possibleposition of the aryl. Phenyl or naphthyl radicals are particularlyadvantageous.

The expression “heteroaryl” represents a 5-, 6- or 7-membered cyclicaromatic radical which contains at least 1, optionally also 2, 3, 4 or 5heteroatoms, wherein the heteroatoms are identical or different and theheterocyclic radical can be unsubstituted or mono- or polysubstituted;in the case of substitution on the heterocyclic radical, thesubstituents can be identical or different and in any desired andpossible position of the heteroaryl. The heterocyclic radical can alsobe part of a bi- or polycyclic system. Preferred heteroatoms arenitrogen, oxygen and sulfur. It is preferable for the heteroaryl radicalto be selected from the group consisting of pyrrolyl, indolyl,furyl(furanyl), benzofuranyl, thienyl(thiophenyl), benzothienyl,benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl,benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,isoxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl,indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl,quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl and oxadiazolyl,wherein bonding to the compounds of the general structure I can takeplace via any desired and possible ring member of the heteroarylradical.

In connection with “alkyl”, in the context of this invention the term“substituted” is understood as meaning substitution of one or morehydrogen radicals by F, Cl, Br, I, —CN, NH₂, NH-alkyl, NH-aryl,NH-heteroaryl, NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl-heteroaryl,NH-alkyl-OH, N(alkyl)₂, N(alkyl-aryl)₂, N(alkyl-heteroaryl)₂,N(cycloalkyl)₂, N(alkyl-OH)₂, NO₂, SH, S-alkyl, S-aryl, S-heteroaryl,S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH, S-alkyl-SH,OH, O-alkyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl,O-cycloalkyl, O-alkyl-OH, CHO, C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl,C(═O)aryl, C(═S)aryl, C(═O))C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl,C(═O)-heteroaryl, C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl,CO₂H, CO₂-alkyl, CO₂-alkyl-aryl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NHaryl,C(═O)NH-cycloalkyl, C(═O)N(alkyl)₂, C(═O)N(alkyl-aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(cycloalkyl)₂, SO-alkyl, SO₂-alkyl,SO₂NH₂, SO₃H, PO(O—C₁₋₆-alkyl)₂, Si(C₁₋₆-alkyl)₃, Si(C₃₋₈-cycloalkyl)₃,Si(CH₂—C₃₋₈-cycloalkyl)₃, Si(phenyl)₃, cycloalkyl, aryl or heteroaryl,wherein polysubstituted radicals are to be understood as meaning thoseradicals which are poly-, e.g. di- or trisubstituted either on differentor on the same atoms, for example trisubstituted on the same C atom asin the case of CF₃ or —CH₂CF₃, or at various places as in the case of—CH(OH)—CH═CH—CHCl₂. The polysubstitution can be by the same or bydifferent substituents. A substituent can optionally also in its turn besubstituted; thus, —Oalkyl also includes, inter alfa,—O—CH₂—CH₂—O—CH₂—CH₂—OH.

In the context of this invention, with reference to “aryl”, “heteroaryl”and “cycloalkyl”, “mono- or polysubstituted” is understood as meaningmono- or poly-, e.g. di-, tri- tetra- or pentasubstitution of one ormore hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH₂,NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl,NH-cycloalkyl, NH-alkyl-OH, N(alkyl)₂, N(alkyl-aryl)₂,N(alkyl-heteroaryl)₂, N(cycloalkyl)₂, N(alkyl-OH)₂, NO₂, SH, S-alkyl,S-cycloalkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl,S-cycloalkyl, S-alkyl-OH, S-alkyl-SH, OH, O-alkyl, O-cycloalkyl, O-aryl,O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, O-cycloalkyl,O-alkyl-OH, CHO, C(═O)C₁₋₆-alkyl, C(═S)C₁₋₆-alkyl, C(═O)aryl, C(═S)aryl,C(═O)—C₁₋₆-alkyl-aryl, C(═S)C₁₋₆-alkyl-aryl, C(═O)-heteroaryl,C(═S)-heteroaryl, C(═O)-cycloalkyl, C(═S)-cycloalkyl, CO₂H, CO₂-alkyl,CO₂-alkyl-aryl, C(═O)NH₂, C(═O)NH-alkyl, C(═O)NHaryl,C(═O)NH-cycloalkyl, C(═O)N(alkyl)₂, C(═O)N(alkyl=aryl)₂,C(═O)N(alkyl-heteroaryl)₂, C(═O)N(cycloalkyl)₂, S(O)-alkyl, S(O)-aryl,SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₃H, CF₃, ═O, ═S; alkyl, cycloalkyl, aryland/or heteroaryl; on one or optionally different atoms (wherein asubstituent can optionally in its turn be substituted). Thepolysubstitution here is by the same or by different substituents.

The term salt is to be understood as meaning any form of the activecompound according to the invention in which this assumes an ionic formor is charged and is coupled with a counter-ion (a cation or anion) oris in solution. This is also to be understood as meaning complexes ofthe active compound with other molecules and ions, in particularcomplexes which are complexed via ionic interactions. In particular, bythese there are understood (and this is also a preferred embodiment ofthis invention) physiologically acceptable salts, in particularphysiologically acceptable salts with cations or bases andphysiologically acceptable salts with anions or acids or also a saltformed with a physiologically acceptable acid or a physiologicallyacceptable cation.

In the context of this invention, the term physiologically acceptablesalt with anions or acids is understood as meaning at least one of thecompounds according to the invention—usually protonated, for example onthe nitrogen—as the cation with at least one anion, which arephysiologically acceptable—especially when used in humans and/ormammals. In particular, in the context of this invention by this thereis understood the salt formed with a physiologically acceptable acid,namely salts of the particular active compound with inorganic or organicacids which are physiologically acceptable—especially when used inhumans and/or mammals. Examples of physiologically acceptable salts ofparticular acids are salts of: hydrochloric acid, hydrobromic acid,sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalicacid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaricacid, lactic acid, citric acid, glutamic acid, saccharic acid,monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid,α-liponic acid, acetylglycine, acetylsalicylic acid, hippuric acidand/or aspartic acid. The hydrochloride salt, the citrate and thehemicitrate are particularly preferred.

In the context of this invention, the term salt formed with aphysiologically acceptable acid is understood as meaning salts of theparticular active compound with inorganic or organic acids which arephysiologically acceptable—especially when used in humans and/ormammals. The hydrochloride and the citrate are particularly preferred.Examples of physiologically acceptable acids are: hydrochloric acid,hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid,fumaric acid, lactic acid, citric acid, glutamic acid, saccharic acid,monomethylsebacic acid, 5-oxo-proline, hexane-1-sulfonic acid, nicotinicacid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid,α-liponic acid, acetylglycine, acetylsalicylic acid, hippuric acidand/or aspartic acid.

In the context of this invention, the term physiologically acceptablesalt with cations or bases is understood as meaning salts of at leastone of the compounds according to the invention—usually of a(deprotonated) acid—as the anion with at least one preferably inorganiccation which are physiologically acceptable—especially when used inhumans and/or mammals. The salts of the alkali metals and alkaline earthmetals and also ammonium salts are particularly preferred, butespecially (mono-) or (di-)sodium, (mono-) or (di-)potassium, magnesiumor calcium salts.

In the context of this invention, the term salt formed with aphysiologically acceptable cation is understood as meaning salts of atleast one of the particular compounds as the anion with at least oneinorganic cation which is physiologically acceptable—especially whenused in humans and/or mammals. The salts of the alkali metals andalkaline earth metals and also ammonium salts are particularlypreferred, but especially (mono-) or (di-)sodium, (mono-) or(di-)potassium, magnesium or calcium salts.

For a preferred embodiment of the spirocyclic cyclohexane derivativesaccording to the invention,

-   R¹ and R² independently of one another represent H, C₁₋₅-alkyl,    branched or unbranched, saturated or unsaturated, unsubstituted or    mono- or polysubstituted, or CHO,-   R³ represents phenyl, benzyl or phenethyl, in each case    unsubstituted or mono- or polysubstituted on the ring-   R⁵ represents H, C₁₋₅-alkyl, branched or unbranched, substituted or    mono- or polysubstituted, COOR¹³,-   R⁶ represents H or C₁₋₅-alkyl,-   R⁷, R⁸, R⁹ and R¹⁰ independently of one another represent H;    C₁₋₅-alkyl, branched or unbranched, unsubstituted or mono- or    polysubstituted; F, Cl, Br, I, OH, OCH₃, NH₂, COOH, COOCH₃, NHCH₃,    N(CH₃)₂, NO₂, SO₃H, SO₂NH₂, pyridyl or phenyl.

Compounds which are preferred according to the invention are alsospirocyclic cyclohexane derivatives of the general formula I wherein Wrepresents NR⁴, O or S and X denotes O, S, SO, SO₂ or NR¹⁷,

-   R¹ and R² independently of one another represents H; C₁₋₄-alkyl,    branched or unbranched, mono- or polysubstituted or unsubstituted;    or CHO-   R³ represents (CH₂)_(n)-aryl, in each case unsubstituted or mono- or    polysubstituted on the aryl, where n=0-2,-   R⁴ represents H; C₁₋₃-alkyl, mono- or polysubstituted or    unsubstituted; CO(CH₂)_(m)H, where m=0 to 2, and/or-   R⁵ and R⁶ in each case represent H and/or-   R⁷, R⁸, R⁹ and R¹⁰ independently of one another represent H;    C₁₋₅-alkyl, OC₁₋₃-alkyl, in each case branched or unbranched,    saturated or unsaturated, unsubstituted or mono- or polysubstituted;    F, Cl, Br, I, CF₃, OH, SH, SCH₃, OCH₃, NH₂, COOH, COOCH₃, NHCH₃,    N(CH₃)₂, NO₂, SO₃H, SO₂NH₂, pyridyl or phenyl.    Compounds in which W represents NR⁴ and X represents O, NH or NCOR¹²    are particularly preferred.

For a particularly preferred embodiment of the spirocyclic cyclohexanederivatives according to the invention R¹ and R² independently of oneanother denote H or CH₃, with the proviso that R¹ and R² do notsimultaneously denote H.

For a particularly preferred embodiment of the spirocyclic cyclohexanederivatives according to the invention, R³ denotes phenyl, benzyl orphenethyl, in each case unsubstituted or mono- or polysubstituted on thering. In particular, R³ denotes phenyl, benzyl, phenethyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl,4-chlorophenyl, 3-chlorophenyl, 2-bromophenyl, 3-bromophenyl,4-bromophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 3-trifluoromethylphenyl, 2-ethylphenyl,3-ethylphenyl, 4-ethylphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,2,4-dichlorophenyl, 2,3-difluorophenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 2,4-difluorophenyl2-fluoro-3-chlorophenyl,2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl,2-fluoro-4-chlorophenyl, 4-fluoro-3-chlorophenyl,4-fluoro-3-methylphenyl, 4-tert-butylphenyl, 4-fluoro-3-chlorophenyl,4-bromo-3-fluorophenyl, 3,5-bis(trifluoromethyl)phenyl,4-chloro-2-trifluoromethylphenyl, 2-methoxy-5-methylphenyl,5-chloro-2-methoxyphenyl, 4-phenoxyphenyl, 2-methylthiophenyl,3-methylthiophenyl, 4-methylthiophenyl, 5-fluoro-2-methoxyphenyl,4-chloro-3-trifluoromethyl or 4-bromo-2-methylphenyl. Very particularlypreferably, R³ denotes phenyl, benzyl, phenethyl, 4-fluorophenyl or3-fluorophenyl.

For a very particularly preferred embodiment of the spirocycliccyclohexane derivatives according to the invention, the radical R⁵represents H, CH₃, COOH, COOCH₃ or CH₂OH, the radical R⁶ represents H;R⁷, R⁸, R⁹ and R¹⁰ independently of one another denote H; C₁₋₅-alkyl,branched or unbranched, unsubstituted or mono- or polysubstituted; F,Cl, Br, I, CF₃, OH, OCH₃, NH₂, COOH, COOCH₃, NHCH₃, N(CH₃)₂, NO₂, SO₃H,SO₂NH₂, pyridyl or phenyl. Preferably the radicals R⁷, R⁸, R⁹ and R¹⁰stand for H; or

one of the radicals R⁷, R⁸, R⁹ and R¹⁰ represents H; C₁₋₅-alkyl,branched or unbranched, unsubstituted or mono- or polysubstituted, inparticular methyl; and F, Cl, Br, I, OH, OCH₃, COOH, COOCH₃, NH₂, NHCH₃,N(CH₃)₂, NO₂, SO₃H, SO₂NH₂, pyridyl or phenyl, while the other radicalsare H, wherein preferably one of the radicals R⁸ or R⁹ is other than H,or two of the radicals R⁷ R⁸, R⁹ and R¹⁰, preferably the radicals R⁸ andR⁹, independently of one another represent H; C₁₋₅-alkyl, branched orunbranched, unsubstituted or mono- or polysubstituted, in particularmethyl; and F, Cl, Br, I, OH, OCH₃, COOH, COOCH₃, NH₂, NHCH₃, N(CH₃)₂,NO₂, SO₃H, SO₂NH₂, pyridyl or phenyl, while the other radicals are H.

Compounds in which W denotes NR⁴, wherein R⁴ represents H, CH₃, C₂H₅,acetyl, phenyl, benzyl or COR¹², and X denotes O, NH or NCOR¹² arefurthermore particularly preferred.

For a very particularly preferred embodiment of the spirocycliccyclohexane derivatives according to the invention R¹ and R²independently of one another denote H or CH₃, in particular CH₃, and R³denotes phenyl.

Very particularly preferred compounds include those selected from thegroup consisting of:

-   1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole    hydrochloride-   1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorene    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorene    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorene    L-tartrate-   1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorene    triflate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dioxafluorene    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene    dihydrochloride-   2-acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene    hydrochloride-   1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indole    hydrochloride-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole    citrate-   6-bromo-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indole    citrate-   6-chloro-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole    citrate-   3,9-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole    citrate-   1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetra-hydro-pyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetra-hydro-pyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole    citrate-   1,1-(3-methylamino-3-phenyl(pentamethylene)-1,3,4,9-tetrahydro-pyrano-[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-3,4-dihydro-1H-2,9-diazafluorene    citrate-   2-acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-3,4-dihydro-1H-2,9-diazafluorene    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluorene    citrate-   2-acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluorene    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-3,4-dihydro-1H-2,9-diazafluorene    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3,4-dihydro-1H-2,9-diazafluorene    dihydrochloride-   1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3-methyl-1,3,4,9-tetrahydro-pyrano-[3,4-b]indole    hemicitrate-   3,6-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetra-hydro-pyrano-[3,4-b]indole    hemicitrate-   3,6-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetra-hydro-pyrano-[3,4-b]indole    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole    citrate-   1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetra-hydro-2-thia-9-azafluorene    methanesulfonate-   1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetra-hydro-2-thia-9-azafluorene    methanesulfonate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-9-oxa-2-thiafluorene    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine    citrate-   6,6-(3-dimethylamino-3-phenylpentamethylene)-1,2,3,4,4a,6,7,11c-octahydro-5-oxa-7-azabenzo[c]fluorene    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-6-bromo-1,3,4,9-tetrahydropyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-6-ol    citrate-   (3S)-1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-3-methoxycarbonyl-1H-2,9-diazafluorene    citrate-   (3S)-1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene-3-methanol    citrate-   1,1-(3-dimethylamino-3-phenylethyl-pentamethylene)-3,4-dihydro-1H-2,9-diazafluorene-   1,1-(3-methylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole    hemicitrate-   1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-3,4-dihydro-1H-2,9-dithiafluorene    methanesulfonate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dithiafluorene    citrate-   1,1-(3-dimethylamino-3-phenylpentamethylene)-2-oxo-1,3,4,9-tetrahydro-2-thia-9-aza-fluorene    citrate-   1,1-(3-dimethylamino-3-benzylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene    and mixtures of two or more of the foregoing.

The substances according to the invention exhibit activity, for example,on the ORL1 receptor, which is relevant in connection with variousdiseases, so that they are suitable as a pharmaceutical activeingredient in a medicament. The invention therefore also relates topharmaceutical compositions comprising at least one spirocycliccyclohexane compound according to the invention and at least onesuitable additive and/or auxiliary substance and/or optionally furtheractive compounds.

In addition to at least one spirocyclic cyclohexane compound accordingto the invention, the pharmaceutical compositions according to theinvention optionally comprise suitable additives and/or auxiliarysubstances, thus also carrier materials, fillers, solvents, diluents,dyestuffs and/or binders, and can be administered as liquid medicamentforms in the form of injection solutions, drops or juices, or assemi-solid medicament forms in the form of granules, tablets, pellets,patches, capsules, plasters/spray plasters or aerosols. The choice ofauxiliary substances etc. and the amounts thereof to be employed dependon whether the pharmaceutical composition is to be administered orally,perorally, parenterally, intravenously, intraperitoneally,intradermally, intramuscularly, intranasally, buccally, rectally orlocally, for example to the skin, the mucous membranes or into the eyes.Formulations in the form of tablets, coated tablets, capsules, granules,drops, juices and syrups are suitable for oral administration, andsolutions, suspensions, easily reconstitutable dry formulations andsprays are suitable for parenteral, topical and inhalatoryadministration. Spirocyclic cyclohexane derivatives according to theinvention in a depot, in a dissolved form or in a plaster, optionallywith the addition of agents which promote penetration through the skin,are suitable formulations for percutaneous administration. Formulationforms which can be used orally or percutaneously can release thespirocyclic cyclohexane derivatives according to the invention in adelayed manner. The spirocyclic cyclohexane derivatives according to theinvention can also be used in parenteral long-term depot forms, such ase.g. implants or implanted pumps. In principle, other further activecompounds known to the expert can be added to the medicaments accordingto the invention.

The amount of active compound to be administered to the patient variesaccording to the weight of the patient, the mode of administration, theindication and the severity of the disease. 0.00005 to 50 mg/kg,preferably 0.001 to 0.5 mg/kg of at least one spirocyclic cyclohexanederivative according to the invention are conventionally administered.

For the all the above forms of the pharmaceutical compositions accordingto the invention, it is particularly preferable if the medicament alsocomprises, in addition to at least one spirocyclic cyclohexanederivative, a further active compound, in particular an opioid,preferably a potent opioid, in particular morphine, or an anaesthetic,preferably hexobarbital or halothane.

In a preferred form of pharmaceutical composition, a spirocycliccyclohexane compound according to the invention contained therein is inthe form of a pure diastereomer and/or enantiomer, a racemate or anon-equimolar or equimolar mixture of the diastereomers and/orenantiomers.

As can be seen from the prior art in the introduction, the ORL1 receptorhas been identified in particular in the pain event. Spirocycliccyclohexane derivatives according to the invention can accordingly beused for the preparation of a pharmaceutical composition for treatmentof pain, in particular acute, neuropathic or chronic pain. The inventiontherefore also relates to the use of a spirocyclic cyclohexanederivative according to the invention for the treatment of pain, inparticular acute, visceral, neuropathic or chronic pain.

The invention also relates to the use of a spirocyclic cyclohexanecompound according to the invention for the treatment of anxiety states,of stress and stress-associated syndromes, depressions, epilepsy,Alzheimer's disease, senile dementia, general cognitive dysfunctions,impaired learning and memory (as a nootropic), withdrawal symptoms,alcohol and/or drug and/or medicament abuse and/or dependency, sexualdysfunctions, cardiovascular diseases, hypotension, hypertension,tinitus, pruritus, migraine, impaired hearing, deficient intestinalmotility, impaired food intake, anorexia, obesity, locomotor disorders,diarrhoea, cachexia, urinary incontinence or as a muscle relaxant,anticonvulsive or anaesthetic or for co-administration with an opioidanalgesic or with an anaesthetic, for diuresis or antinatriuresis,anxiolysis, for modulation of motor activity, for modulation ofneurotransmitter secretion and treatment of associated neurodegenerativediseases, for treatment of withdrawal symptoms and/or for reducing theaddiction potential of opioids.

In one of the above uses, it may be preferable in this context if aspirocyclic cyclohexane derivative used is in the form of a purediastereomer and/or enantiomer, a racemate or a non-equimolar orequimolar mixture of the diastereomers and/or enantiomers.

The invention also provides a method for treatment, in particular in oneof the abovementioned indications, of a non-human mammal or human whichor who requires treatment of pain, in particular chronic pain, byadministration of a therapeutically active dose of a spirocycliccyclohexane derivative according to the invention or of a medicamentaccording to the invention.

The invention also provides a process for the preparation of thespirocyclic cyclohexane derivatives according to the invention asdescribed in the following description and examples. A process which isparticularly suitable in this context is a process, called the mainprocess in the following, for the preparation of a spirocycliccyclohexane derivative according to the invention with the followingsteps, wherein

-   X, W, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ have the meaning given    for compounds according to formula I according to the invention,    and-   R⁰¹ and R⁰² have the meaning given for R¹ and R² for compounds    according to formula I according to the invention and additionally    independently of one another can represent a protective group:

In order to prepare compounds corresponding to formula Ia, ketones ofthe general formula A are reacted with heteroaromatics of the generalformula B, with the addition of acid or trimethylsilyl esters thereof,for example trifluoromethanesulfonic acid trimethylsilyl ester, aceticacid, phosphoric acid, methanesulfonic acid or trifluoroacetic acid, ina suitable solvent, for example dichloroethane, methylene chloride,chloroform, acetonitrile, diethyl ether or nitromethane. The preparationof the ketone intermediate A is carried out, in particular, inaccordance with the following instructions:

-   a. a cyclohexane-1,4-dione according to formula II protected with    the groups S¹ and S², which represent protective groups—for example    substituted or unsubstituted alkyl, in particular (CH₂)_(n), where    n=2-4—is reacted with a cyanide, preferably potassium cyanide or    TMSCN, in the presence of a compound of the formula HNR⁰¹R⁰², to    give a protected N-substituted 1-amino-4-oxo-cyclohexanecarbonitrile    derivative according to formula III;

-    the product optionally subsequently, in any desired sequence and    optionally repeatedly, is acylated, alkylated or sulfonated and/or    in the case of compounds where R⁰¹ and/or R⁰²=protective group a    protective group is split off at least once, and the product    optionally is acylated, alkylated or sulfonated and/or in the case    of a compounds where R⁰¹ and/or R⁰²=H a protective group is    introduced at least once, and the product is optionally acylated,    alkylated or sulfonated,-   b. the aminonitrile according to formula III is reacted with    organometallic reagents, preferably Grignard or organolithium    reagents, of the formula metal-R³, so that a compound according to    formula IV is formed;

-    the product optionally subsequently, in any desired sequence and    optionally repeatedly, is acylated, alkylated or sulfonated and/or    in the case of compounds where R⁰¹ and/or R⁰²=protective group a    protective group is split off at least once, and the product    optionally is acylated, alkylated or sulfonated and/or in the case    of a compounds where R⁰¹ and/or R⁰²=H a protective group is    introduced at least once, and the product is optionally acylated,    alkylated or sulfonated,-   c. the protective groups S¹ and S² on the compound according to    formula IV are split off, so that a 4-substituted    4-aminocyclohexanone derivative according to formula A is formed;

-    the product optionally subsequently, in any desired sequence and    optionally repeatedly, is acylated, alkylated or sulfonated and/or    in the case of compounds where R⁰¹ and/or R⁰²=protective group a    protective group is split off at least once, and the product    optionally is acylated, alkylated or sulfonated and/or in the case    of a compounds where R⁰¹ and/or R⁰²=H a protective group is    introduced at least once, and the product is optionally acylated,    alkylated or sulfonated,-   wherein X, W, R³, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ have the meaning given    for compounds according to formula I according to the invention,    and-   R⁰¹ and R⁰² have the meaning given for R¹ and R² for compounds    according to formula I according to the invention and additionally    independently of one another can represent a protective group:

Alternatively, the preparation can also be carried out in accordancewith the following equation, wherein

-   X, W, R³, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ have the meaning given for    compounds according to formula I according to the invention    and-   R⁰¹ and R⁰² have the meaning given for R¹ and R² for compounds    according to formula I according to the invention and additionally    independently of one another can represent a protective group.

Spirocyclic cyclohexane compounds corresponding to formula I in which Xdenotes NR¹⁷ and R¹⁷ denotes COR¹² or SO₂R¹² can be obtained by reactionof spirocyclic cyclohexane compounds corresponding to formula I in whichX denotes NH by reaction with an anhydride or an acid chloride with theaddition of a base, for example triethylamine. This reaction preferablytakes place under microwave irradiation.

Spirocyclic cyclohexane compounds corresponding to formula I in which Xdenote SO or SO₂ can be obtained by reaction of spirocyclic cyclohexanederivatives of the general formula I in which X denotes S with anoxidizing agent, for example H₂O₂.

Isolation of the compounds according to the invention by columnchromatography with silica gel as the stationary phase and ethylacetate, methanol, ethanol, mixtures of ethyl acetate and methanol orethanol or mixtures of ethyl acetate and diethyl ether as the mobilephase leads to separation of the diastereoisomers of varying polarity.These have been characterized on the basis of their migration timeduring the separation as “most non-polar diastereoisomer” (shortestmigration time) to “most polar diastereoisomer” (longest migrationtime).

EXAMPLES

The following examples serve to illustrate the invention in more detail,but do not limit the general inventive idea. The yields of the compoundsprepared are not optimized. All temperatures are uncorrected.

The term “ether” means diethyl ether, “EA” ethyl acetate and “MC”methylene chloride. The term “equivalents” means equivalent substanceamount, “m.p.” melting point or melting range, “decomp.” decomposition,“RT” room temperature, “abs.” absolute (anhydrous), “rac.” racemic,“conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol. %”percent by volume, “wt. %” percent by weight and “M” is a concentrationstated in moles per liter.

Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt was employed asthe stationary phase for the column chromatography. The thin layerchromatography analyses were carried out with HPTLC precoated plates,silica gel 60 F 254 from E. Merck, Darmstadt. The mixture ratios ofmobile phases for chromatography analyses are always stated involume/volume.

The compounds employed in the following procedures either wereobtainable commercially or their preparation is known from the prior artor has been deduced from the prior art in a manner obvious to thoseskilled in the art of chemical synthesis. The following references areparticularly relevant for this: Jirkovsky et al., J. Heterocycl. Chem.,12, 1975, 937-940; Campaigne et al., J. Heterocycl. Chem., 2, 1965,231-235; Efange et al., J. Med. Chem., 41, 1998, 4486-4491; Ellingboe etal., J. Med. Chem., 35, 1992, 1176-1183; Pearson et al., Aust. J. Chem.,44, 1991, 907-917; Yokohama et al., Chem. Pharm. Bull., 40, 1992,2391-2398; Beck et al., J. Chem. Soc. Perkin 1, 1992, 813-822; Shinadaet al., Tetrahedron Lett., 39, 1996, 7099-7102; Garden et al.,Tetrahedron, 58, 2002, 8399-8412; Lednicer et al., J. Med. Chem., 23,1980, 424-430.

Example 11,1-(3-Dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrochloride, more non-polar diastereoisomer And Example 21,1-(3-Dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrochloride, more polar diastereoisomer And Example 31,1-(3-Dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indoleHemicitrate, more non-polar diastereoisomer

Method A:

Trifluoromethanesulfonic acid trimethylsilyl ester (1 ml, 5 mmoles) wasadded under argon to a solution of 4-dimethylamino-4-phenylcyclohexanone(1.1 g, 5.07 mmoles) and 3-(2-trimethylsilanyloxyethyl)-1H-indole (1.4g, 6.01 mmoles) in MC (30 ml) at −78° C. in the course of 5 min, whilestirring. The mixture was stirred at −78° C. for 1 hour. The mixture wasthen brought to room temperature over a period of 4 hours and stirred atroom temperature for a further 10 hours. For working up, 1 M NaOH (30ml) was added to the reaction mixture and the mixture was stirred for 30min. The organic phase was separated, and the aqueous phase whichremained was extracted with MC (2×30 ml). The combined organic phaseswere washed with 1 M NaOH (1×30 ml) and water (2×30 ml) and dried oversodium sulfate. After the solvent had been distilled off, a yellow solidwas obtained, which was washed with EA. After recrystallization of thecrude product which remained from toluene, the more non-polar isomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole,which had a melting point of 279-284° C., was isolated in a yield of 0.8g. The mother liquor which remained and the EA wash solution wereconcentrated. By means of purification by column chromatography onsilica gel, first with EA/ethanol (volume ratio 8:2) then withEA/ethanol (volume ratio 1:1), it was possible to separate off the morenon-polar compound already isolated (150 mg) and a further more polarisomer. After recrystallization from toluene, the more polar product wasobtained in a yield of 60 mg with a melting point of 230-235° C.

Method B:

Tryptophol (322 mg, 2.0 mmoles) and4-dimethylamino-4-phenylcyclohexanone (435 mg, 2.0 mmoles) weredissolved under argon in a mixture of acetic acid (4 ml) and 85 percentstrength by weight phosphoric acid (1 ml), while stirring and coolingwith ice. The mixture was stirred overnight at RT. The solid formed wasfiltered off with suction and washed with methanol. Only the more polarof the two possible diastereoisomers was obtained as a white solid in ayield of 600 mg with a melting point of 280-284° C.

Method C:

4-Dimethylamino-4-phenylcyclohexanone (868 mg, 4 mmoles) and tryptophol(644 mg, 4 mmoles) were initially introduced into abs. MC (30 ml) underargon. Triethylamine (0.07 ml, 0.5 mmoles) was added to the solution.Trifluoromethanesulfonic acid trimethylsilyl ester (0.9 ml, 4.7 mmoles)was then added very rapidly. The mixture was stirred at RT for 20 h. Forworking up, 1 M NaOH (50 ml) was added to the reaction mixture and themixture was stirred for 30 min. The organic phase was separated, and theaqueous phase which remained was extracted with MC (3×30 ml). Thecombined organic phases were washed with water (2×30 ml) and dried oversodium sulfate. Methanol (40 ml) was added to the largely solid residueobtained after the solvent had been distilled off, and the mixture washeated, and stirred for 15 hours. The suspended solid is the morenon-polar diastereoisomer. The more polar diastereoisomer was in themethanolic solution. The more non-polar isomer was obtained in a yieldof 1.20 g with a melting point of 278-282° C. Recrystallization fromisopropanol gave cotton wool-like crystals which contained oneequivalent of isopropanol. The melting point of the recrystallizedproduct was 289-293° C.

Method D:

4-Dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmoles) and tryptophol(322 mg, 4 mmoles) were initially introduced into abs. MC (20 ml) underargon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.4 ml, 2.07mmoles) was then added very rapidly. The mixture was stirred at RT for18 h. For working up, 1 M NaOH (20 ml) was added to the reaction mixtureand the mixture was stirred for 30 min. The organic phase was separated,and the aqueous phase which remained was extracted with MC (3×30 ml).The combined organic phases were washed with water (2×30 ml) and driedover sodium sulfate. Methanol (20 ml) was added to the largely solidresidue obtained after the solvent had been distilled off, and themixture was heated, and stirred for 15 hours. The suspended solid is themore non-polar diastereoisomer. The more polar product was in themethanolic solution. The more non-polar diastereoisomer was obtained ina yield of 571 mg with a melting point of 284-286° C.

Method E:

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and3-(2-trimethylsilanyloxyethyl)-1H-indole (699 mg, 3 mmoles) weredissolved in abs. MC (20 ml) under argon. Trifluoromethanesulfonic acid(0.28 ml, 3.16 mmoles) was then added very rapidly. The mixture wasstirred at RT for 20 hours. For working up, 1 M NaOH (20 ml) was addedto the reaction mixture and the mixture was stirred for 30 min. Theorganic phase was separated, and the aqueous phase which remained wasextracted with MC (3×30 ml). The combined organic phases were washedwith water (2×30 ml) and dried over sodium sulfate. The solid residueobtained after the solvent had been distilled off was the more non-polardiastereoisomer (800 mg).

Example 1 Hydrochloride of the More Non-Polar Diastereoisomer

For preparation of the hydrochloride, the more non-polar diastereoisomerof1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole(500 mg, 1.38 mmoles) was dissolved in 2-butanone (40 ml),chlorotrimethylsilane (250 μl, 1.98 mmoles) was added and the mixturewas stirred at RT for 3 hours. The resulting solid was filtered out withsuction. It was possible to obtain the hydrochloride of the morenon-polar diastereoisomer in this way in a yield of 420 mg as a whitesolid with a melting point of 278-280° C.

Investigations of cardiovascular tolerability were carried out forExample 1. It was found that compared with the two opioids fentanyl andsufentanil, which are employed clinically, the compound of Example 1 hasadvantages in respect of cardiovascular tolerability.

Example 2 Hydrochloride of the More Polar Diastereoisomer

Chlorotrimethylsilane (25 μl, 0.198 mmoles) was added to a solution ofthe more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole(50 mg, 0.138 mmoles) in 2-butanone (10 ml). After a reaction time of 2hours, it was possible to isolate the precipitated hydrochloride of themore polar diastereoisomer in a yield of 36 mg with a melting point of271-272° C.

Example 3 Hemicitrate of the More Non-Polar Diastereoisomer

For preparation of the hemicitrate, the more non-polar diastereoisomerof1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole(1.2 g, 3.33 mmoles) was dissolved in hot ethanol (350 ml), and asimilarly hot solution of citric acid (1.2 g, 6.25 mmoles) in ethanol(30 ml) was added. After cooling, the mixture was left at approx. 10° C.for 4 hours. The resulting solid was filtered out with suction. It waspossible to obtain the hemicitrate in this way in a yield of 1.05 g as awhite solid with a melting point of 259-265° C.

Example 41,1-(3-Dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenehemicitrate, more non-polar diastereoisomer And Example 51,1-(3-Dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenecitrate, more polar diastereoisomer

Method A:

4-Dimethylamino-4-phenylcyclohexanone (326 mg, 1.5 mmoles) and2-(1H-indol-3-yl)ethanethiol (266 mg, 1.5 mmoles) were initiallyintroduced into abs. MC (10 ml) under argon. The methanesulfonic acidtrimethylsilyl ester (254 μl, 1.65 mmoles) was then added. The mixturewas stirred at RT for 4 days. For working up, the methanesulfonate whichhad precipitated out was filtered off with suction and washed with MC(3×0.5 ml). The methanesulfonate was obtained in a yield of 306 mg as awhite solid with a melting point of 243-245° C.—The MC phase was workedup under alkaline conditions (1 M NaOH, 30 ml, vigorous stirring for 1hour), the phases were separated, and the MC phase was concentrated. Theresidue was covered with a layer of abs. ethanol (10 ml), and themixture was stirred under reflux for 30 min. After standing at roomtemperature for several hours, the precipitate was filtered out withsuction, washed with ethanol (4×1 ml) and then dried. A mixture of themore non-polar and more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenewas obtained in a yield of 182 mg.

Method B:

4-Dimethylamino-4-phenylcyclohexanone (386.5 mg, 1.78 mmoles) and2-(1H-indol-3-yl)ethanethiol (315 mg, 1.78 mmoles) were dissolved inglacial acetic acid (8 ml) under argon. The mixture was cooled to 4° C.and 85 percent strength by weight phosphoric acid (2 ml) was addeddropwise. Thereafter, the mixture was stirred at room temperature for 20hours. For working up, the suspension formed was cooled to 5° C., 1 MNaOH (60 ml) was added and the mixture was stirred at room temperaturefor 1 hour. After addition of MC (50 ml), the mixture was stirred atroom temperature for 2 hours. The clear phases were separated. Theaqueous phase was extracted with MC (3×10 ml). The combined organicphases were dried over sodium sulfate, and the MC was distilled off. Oneof the two diastereoisomers of1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenewas obtained in this way as a white solid in a yield of 603 mg with amelting point of 236-238° C.

Example 4 Hemicitrate of the More Non-Polar Diastereoisomer

The diastereoisomer mixture obtained by Method A (172 mg, 0.457 mmoles)was dissolved in hot ethanol (130 ml), citric acid (88.6 mg, 0.461mmoles) was added and the mixture was stirred at 65° C. for 10 min.After cooling to RT, the mixture was stirred for 20 h. The solid formedwas filtered off with suction, washed with cold ethanol (2×0.5 ml) andthen dried. 85 mg of the hemicitrate of the more non-polardiastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenewere obtained (m.p. 241-243° C.).

Example 5 Citrate of the More Polar Diastereoisomer

The ethanolic mother liquor obtained according to Example 4 was reducedto 25 ml of solution, 20 ml Et₂O were added and the mixture was stirredat RT for 1 h. The precipitate was filtered off with suction, washedwith Et₂O (3×2 ml) and dried (62 mg, m.p. 165-169° C., diastereoisomermixture). A white solid were obtained again from the mother liquor byaddition of a further 50 ml diethyl ether. This was also filtered outwith suction, washed with Et₂O (3×2 ml) and dried. 32 mg of the citrateof the more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpenta-methylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenewere obtained (m.p. 155-160° C.).

Example 61,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluoreneL-tartrate

Method A:

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and2-(benzo[b]thiophen-3-yl)ethanol (178 mg, 1 mmole) were initiallyintroduced into abs. MC (10 ml) under argon. Trifluoromethanesulfonicacid trimethylsilyl ester (245 μl, 1.1 mmoles) was then added. Themixture was stirred at room temperature for 24 hours. After this time,the reaction mixture was pale brown in color and clear. For working up,10 g ice were added, and the aqueous phase was adjusted to pH 11 with 1M NaOH. The phases were separated. The aqueous phase was extracted withMC (3×10 ml). The organic phases were combined, washed with water (2×3ml), dried and concentrated.1,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorenewas obtained from the residue, by extraction by stirring with ethanol(15 ml) at the boiling point, as a diastereoisomerically pure whitesolid in a yield of 322 mg with a melting point of 219-222° C.

Method B:

4-Dimethylamino-4-phenylcyclohexanone (231.4 mg, 1.06 mmoles) and2-(benzo[b]thiophen-3-yl)ethanol (190 mg, 1.06 mmoles) were initiallyintroduced into abs. MC (10 ml) under argon. Methanesulfonic acid (130μl, 2 mmoles) was then added. The mixture was stirred at roomtemperature for 20 hours. After this time, the reaction mixture was palebrown in color and clear. For working up, 20 ml 1 M NaOH were added andthe mixture was stirred at RT for 30 min. The phases were separated. Theaqueous phase (pH 11) was extracted with MC (3×10 ml). The organicphases were combined, washed with water (4×10 ml), dried andconcentrated.1,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorenewas obtained from the residue, by extraction by stirring with ethanol(10 ml) at the boiling point, as a diastereoisomerically pure whitesolid in a yield of 340 mg with a melting point of 218-222° C. The samediastereoisomer was obtained as by Method A.

Example 6 L-Tartrate

1,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorene(110 mg, 0.29 mmole) was dissolved in hot ethanol (50 ml), and a 0.1 Msolution of L-tartaric acid (3.2 ml, 0.32 mmole) in ethanol was added.After cooling to room temperature, the mixture was stirred for 24 hours.After 24 hours, the solvent was concentrated to a residual volume ofapprox. 10 ml. The solid which had now precipitated out was filtered outwith suction at room temperature, washed with ethanol (3×1 ml) anddried. The L-tartrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorenewas obtained in this way in a yield of 130 mg as a white solid with amelting point of 220-224° C.

Example 71,1-(3-Dimethylamino-3-(4-fluorophenyl)pentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorenetriflate

4-Dimethylamino-4-(4-fluorophenyl)cyclohexanone (470.6 mg, 2 mmoles) and2-(benzo[b]thiophen-3-yl)ethanol (356.5 mg, 2 mmoles) were initiallyintroduced into abs. MC (20 ml) under argon. Trifluoromethane-sulfonicacid trimethylsilyl ester (0.425 ml, 2.2 mmoles) was then added. Themixture was stirred at RT for 64 h. For working up, the solid which hadprecipitated out was filtered out with suction, washed with MC (3×1 ml)and dried. The triflate of1,1-(3-dimethylamino-3-(4-fluorophenyl)-pentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorenewas obtained in a yield of 383 mg as a diastereoisomerically pure whitesolid with a melting point of 212-215° C.

Example 81,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dioxafluorenehemicitrate

4-Dimethylamino-4-phenylcyclohexanone (868 mg, 4 mmoles) and2-(benzofuran-3-yl)ethanol (648 mg, 4 mmoles) were initially introducedinto abs. MC (20 ml) under argon. Trifluoromethanesulfonic acidtrimethylsilyl ester (0.8 ml, 4.14 mmoles) was then added very rapidly.The mixture was stirred at room temperature for 2 hours. For working up,1 M NaOH (20 ml) was added to the reaction mixture and the mixture wasstirred for 30 min. The organic phase was separated, and the aqueousphase which remained was extracted with MC (3×20 ml). The combinedorganic phases were washed with water (2×30 ml) and dried over sodiumsulfate. Methanol (30 ml) was added to the solid residue obtained afterthe solvent had been distilled off, and the mixture was heated, andstirred for 15 hours. The content which was insoluble in methanol wasfiltered out with suction. One of the two possible diastereoisomers of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dioxafluorenewas obtained in this manner in a yield of 650 mg with a melting point of206-208° C. For preparation of the hemicitrate, the crude productobtained (600 mg, 1.66 mmoles) was dissolved in hot ethanol (100 ml),and a similarly hot solution of citric acid (600 mg, 3.12 mmoles) inethanol (20 ml) was added. After cooling to approx. 5° C., a solidprecipitated out and, after standing for 2 hours, was filtered out withsuction. The hemicitrate of1,1-(3-dimethyl-amino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dioxafluorenewas obtained in this way in a yield of 626 mg as a white solid (m.p.:201-202° C.).

Example 91,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenedihydrochloride, more non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (1.09 g, 5 mmoles) and tryptamine(800 mg, 5 mmoles) were dissolved in dry 1,2-dichloroethane (50 ml) withexclusion of oxygen. Trifluoroacetic acid (770 μl, 10 mmoles) and sodiumsulfate (2 g) were added to this mixture, while stirring. After areaction time of 15 hours, trifluoroacetic acid (3 ml) was again addedto the reaction mixture and the mixture was stirred at room temperaturefor a further 16 hours. For working up, the solvent was distilled off,and water (20 ml) was added to the residue. This aqueous phase wasadjusted to pH 11 with NaOH (5 mol/l) and extracted with EA (3×30 ml).The organic phase was dried with sodium sulfate and concentrated. Theproduct was a mixture of the two diastereoisomeric1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenes,which it was possible to separate by chromatography on silica gel withmethanol. The more non-polar product was obtained in a yield of 557 mg(31%) as a white solid. For preparation of the dihydrochloride, these557 mg were suspended in 2-butanone (7 ml), and chlorotrimethylsilane(500 μl, 3.75 mmoles) was added. The resulting solid was filtered outwith suction and dried. The dihydrochloride of the more non-polardiastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 670 mg as a white solid with amelting point of 243-247° C.

Example 101,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenedihydrochloride, more polar diastereoisomer

As described for Example 9, 449 mg of the more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenewere also obtained as a white solid. For preparation of thedihydrochloride, these 449 mg were suspended in 2-butanone (7 ml), andchlorotrimethylsilane (417 μl, 3.13 mmoles) was added. The solid therebyformed was filtered off with suction and dried. The dihydrochloride ofthe more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 540 mg as a white solid with amelting point of 244-246° C.

Example 112-Acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenehydrochloride, more non-polar diastereoisomer

Method A:

The more non-polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene(375 mg, 1.04 mmoles) was dissolved in pyridine (10 ml). Thereafter,acetic anhydride (985 μl, 10.43 mmoles) was added dropwise, and themixture was stirred at room temperature for 2 days. For working up,pyridine was distilled off and water (10 ml) was added to the residue.The mixture was adjusted to pH 11 with 5 M NaOH and extracted with EA(3×15 ml). The organic phase was dried with sodium sulfate andevaporated. The residue was purified by column chromatography on silicagel with methanol. The acetamide of the more non-polar diastereoisomerof1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 356 mg as a white solid. Forpreparation of the hydrochloride, these 356 mg were suspended in2-butanone (5 ml), and chlorotrimethylsilane (178 μl, 1.34 mmoles) wasadded. The resulting solid was filtered out with suction and dried. Thehydrochloride of the more non-polar diastereoisomer of2-acetyl-1,1-(3-dimethylamino-3-phenylpenta-methylene)-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 388 mg as a white solid with amelting point of 220-223° C.

Method B:

Triethylamine (0.31 ml; 2.23 mmoles) and then acetic anhydride (0.21 ml;2.23 mmoles) were added to a suspension of the more non-polardiastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene(80 mg; 0.22 mmole) in 15 ml acetonitrile. The reaction mixture washeated at 130° C. in a closed vessel in a microwave oven (MLS-Ethos 1600from MLS GmbH, Leutkirch im Allgäu, Germany) for 10 minutes at 1,000watt. 5 M aqueous potassium hydroxide solution (6 ml) and water (4 ml)were then added, and the aqueous phase was extracted with methylenechloride (3×10 ml). After the organic phase had been separated and driedwith sodium sulfate and the solvent had been removed in vacuo, furtherpurification was carried out by column chromatography on silica gel withEA and methanol. 49 mg of the acetylated base were obtained. It waspossible to carry out precipitation of the hydrochloride as describedunder Method A.

Example 122-Acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenehydrochloride, more polar diastereoisomer

The more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene(375 mg, 1.04 mmoles) was dissolved in pyridine (10 ml). Thereafter,acetic anhydride (985 μl, 10.43 mmoles) was added dropwise and themixture was stirred at room temperature for 2 days. For working up,pyridine was distilled off and water H₂O (10 ml) was added to theresidue. The mixture was adjusted to pH 11 with 5 M NaOH and extractedwith EA (3×15 ml). The organic phase was dried with sodium sulfate andevaporated. The product was purified by column chromatography on silicagel with methanol. The acetamide of the more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 339 mg as a white solid. Forpreparation of the hydrochloride, these 339 mg were suspended in2-butanone (5 ml), and chlorotrimethylsilane (168 μl, 1.27 mmoles) wasadded. The resulting solid was filtered off with suction and dried. Thehydrochloride of the more polar diastereoisomer of2-acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 370 mg as a white solid with amelting point of 186-188° C.

Example 131,1-(3-Dimethylamino-3-phenylpentamethylene)-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indolehydrochloride

4-Dimethylamino-4-phenylcyclohexanone (550 mg, 2.5 mmoles) and5-methoxy-3-(2-trimethylsilanyloxy-ethyl)-1H-indole (789 mg, 3 mmoles)were initially introduced into abs. MC (30 ml) under argon. The solutionwas cooled to approx. 0° C. with the aid of an ice/sodium chloridemixture, and trifluoromethanesulfonic acid trimethylsilyl ester (0.5 ml,2.5 mmoles) was added in the course of 5 min, while stirring. Themixture was cooled in the ice-bath for a further 3 hours, brought toroom temperature in the course of approx. 1 hour and then stirred atroom temperature for a further 10 hours. For working up, 1 M NaOH (30ml) was added to the reaction mixture and the mixture was stirred for 30min. The organic phase was separated, and the aqueous phase whichremained was extracted with MC (2×30 ml). The combined organic phaseswere washed with water (2×30 ml) and dried over sodium sulfate. Methanol(70 ml) was added to the largely solid residue obtained after thesolvent had been distilled off, the mixture was stirred for 2 hours, andthe resulting suspension was filtered. 478 mg of one of the two possiblediastereoisomers of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indolewere obtained with a melting point of 244-246° C. 430 mg of this weredissolved in 2-butanone (25 ml), chlorotrimethylsilane (250 μl, 1.98mmoles) was added, and the mixture was stirred at room temperature for30 minutes. The resulting solid was filtered out with suction. Thehydrochloride of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this way in a yield of 396 mg as a white solid with amelting point of 279-280° C.

Example 141,1-(3-Dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate, more non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmoles) and3-(2-trimethylsilanyloxypropyl)-1H-indole (592 mg, 2.4 mmoles) wereinitially introduced into abs. MC (15 ml) under argon. The solution wascooled to approx. 0° C. with the aid of an ice/sodium chloride mixture,and trifluoromethanesulfonic acid trimethylsilyl ester (0.39 ml, 2mmoles) was added in the course of 5 min, while stirring. The mixturewas cooled in the ice-bath for a further 4 hours. After warming to roomtemperature, it was stirred for a further 20 hours. For working up, 1 MNaOH (20 ml) was added to the reaction mixture and the mixture wasstirred for 30 min. The organic phase was separated, and the aqueoussolution which remained was extracted with MC (2×30 ml). The combinedorganic phases were washed with water (2×30 ml) and dried over sodiumsulfate. Methanol (70 ml) was added to the largely solid residueobtained after the solvent had been distilled off, and the mixture wasstirred for 2 hours. A suspension was formed, from which the morenon-polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,which is sparingly soluble in methanol, was obtained by filtration in ayield of 127 mg as a white solid with a melting point of 306-312° C. 94mg of this were dissolved in hot ethanol (50 ml), and a similarly hotsolution of citric acid (48 mg, 0.25 mmole) in ethanol (10 ml) wasadded. After cooling, the mixture was left to stand for 3 days. Theresulting solid was filtered out with suction. It was possible to obtainthe hemicitrate of the more non-polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolein this way in a yield of 67 mg as a white solid (decomp. from 280° C.).

Example 151,1-(3-Dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate, more polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (149 mg, 0.69 mmole) and1-(1H-indol-3-yl)propan-2-ol (120 mg, 0.69 mmole) were dissolved inconc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowlyadded dropwise to this mixture. After a reaction time of 5 min, a redsolution was formed, from which a white solid precipitated out. Themixture was stirred at room temperature for 16 hours. For working up,the mixture was diluted with water (20 ml), adjusted to pH 11 with 5 MNaOH and extracted with MC (3×20 ml). The organic phase was dried withsodium sulfate and evaporated. The residue chiefly consisted of the morepolar diastereoisomer, which it was possible to obtain in a yield of 260mg as a white solid. For preparation of the citrate, these 260 mg, 0.69mmole) were suspended in hot ethanol (20 ml), and a similarly hotsolution of citric acid (133 mg, 0.69 mmole) in ethanol (5 ml) wasadded. The substance thereby dissolved completely and no longerprecipitated out even on cooling to approx. 5° C. Ethanol was removed ona rotary evaporator, and it was possible to obtain the citrate of themore polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolein this way in a yield of 392 mg as a white solid (m.p.: 160-165° C.).

Example 166-Bromo-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and5-bromo-3-(2-trimethylsilanyloxypropyl)-1H-indole (975 mg, 3 mmoles)were initially introduced into abs. MC (15 ml) under argon. The solutionwas cooled to approx. 0° C. with the aid of an ice/sodium chloridemixture, and trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml,3.1 mmoles) was added in the course of 5 min, while stirring. Themixture was cooled in the ice-bath for a further 2 hours. After warmingto room temperature, it was stirred for a further 20 hours. For workingup, 1 M NaOH (30 ml) was added to the reaction mixture and the mixturewas stirred for 30 min. The organic phase was separated, and the aqueoussolution which remained was extracted with MC (2×30 ml). The combinedorganic extracts were washed with water (2×30 ml) and dried over sodiumsulfate. Methanol (70 ml) was added to the largely solid residueobtained after the solvent had been distilled off, and the mixture wasstirred for 1 hour. The material which had not dissolved was filteredout with suction. It proved to be one of the two possible racemicdiastereoisomers of6-bromo-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,which was obtained in this way in a yield of 260 mg (19%) as a whitesolid with a melting point of 287-293° C. in the pure form. 250 mg ofthis were dissolved in hot ethanol (120 ml), and a similarly hotsolution of citric acid (120 mg, 0.62 mmole) in ethanol (10 ml) wasadded. The mixture was cooled and left at approx. 10° C. for 20 hours.The solid formed was filtered out with suction. It was possible toobtain the hemicitrate of6-bromo-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indolein this way in a yield of 188 mg as a white solid (m.p. from 230° C.crystal conversion, from 290° C. sublimation).

Example 171,1-(3-Dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate, more non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and5-nitro-3-(2-trimethylsilanyloxy-propyl)-1H-indole (876 mg, 3 mmoles)were initially introduced into abs. MC (20 ml) under argon. The solutionwas cooled to approx. 0° C. with the aid of an ice/sodium chloridemixture, and trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml,3.1 mmoles) was added in the course of 5 min, while stirring. Themixture was cooled in the ice-bath for a further 2 h. After warming toRT, it was stirred for a further 70 h. For working up, 1 M NaOH (50 ml)and MC (20 ml) were added to the reaction mixture and the mixture wasstirred for 30 min. The organic phase was separated, and the aqueoussolution which remained was extracted with MC (3×40 ml). The combinedorganic phases were washed with water (2×30 ml) and dried over sodiumsulfate. Methanol (30 ml) was added to the vitreous residue obtainedafter the solvent had been distilled off, and the mixture was stirredfor 1 h. The solid which was insoluble in methanol proved to be adiastereoisomer mixture. It was possible to separate the two racemicdiastereoisomers by separation by column chromatography on silica gel(mobile phase: EA). The more non-polar product was obtained in a yieldof 154 mg as a white solid with a melting point of 252-265° C. in thepure form. 134 mg of this were dissolved in hot ethanol (150 ml), and asimilarly hot solution of citric acid (110 mg, 0.57 mmole) in ethanol(20 ml) was added. The mixture was cooled and left at approx. 10° C. for20 h. The solid formed was filtered off with suction. The citrate of themore non-polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this way in a yield of 117 mg with a melting point of258-262° C.

Example 181,1-(3-Dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate, more polar diastereoisomer

As described for Example 17, 120 mg of the more polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indolewith a melting point of 230-240° C. were also obtained. These 120 mgwere dissolved in hot ethanol (120 ml), and a similarly hot solution ofcitric acid (100 mg, 0.52 mmole) in ethanol (10 ml) was added. Thesolution was cooled and concentrated to dryness in vacuo. The residueobtained was taken up in water (10 ml), the citrate being obtained as acrystalline solid. After filtration and drying, the citrate of the morepolar diastereoisomer of1,1-(3-dimethylamino-3-phenylpenta-methylene)-3-methyl-6-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in a yield of 76 mg with a melting point of 190-192° C.

Example 196-Chloro-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate, more non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (600 mg, 2.76 mmoles) and5-chloro-3-(2-trimethylsilanyloxypropyl)-1H-indole (846 mg, 3 mmoles)were initially introduced into abs. MC (30 ml) under argon. The solutionwas cooled to approx. 0° C. with the aid of an ice/sodium chloridemixture, and trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml,3.1 mmoles) was added in the course of 5 min, while stirring. Themixture was cooled in the ice-bath for a further 2 hours. After warmingto room temperature, it was stirred for a further 18 hours. For workingup, 1 M NaOH (30 ml) was added to the reaction mixture and the mixturewas stirred for 30 min. The organic phase was separated, and the aqueoussolution which remained was extracted with MC (2×30 ml). The combinedorganic phases were washed with water (2×30 ml) and dried over sodiumsulfate. Methanol (50 ml) was added to the oily residue obtained afterthe solvent had been distilled off, and the mixture was stirred for 1hour. A suspension was formed. The solid, which was insoluble inmethanol, was separated, and it was possible to obtain the morenon-polar diastereoisomer of6-chloro-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,by separation by column chromatography on silica gel (mobile phase: EA),in a yield of 60 mg as a white solid (m.p.: from 180° C.). 55 mg of thiswere dissolved in hot ethanol (40 ml), and a similarly hot solution ofcitric acid (50 mg, 0.26 mmole) in ethanol (10 ml) was added. Thesolution was cooled, and concentrated to dryness in vacuo. The residueobtained was taken up in water (10 ml), the citrate of the morenon-polar diastereoisomer of6-chloro-1,1-(3-dimethylamino-3-phenylpenta-methylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolebeing obtained as a crystalline solid. After filtration and drying, 36mg with a melting point of 185-195° C. were obtained.

Example 206-Chloro-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate, more polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and1-(5-chloro-1H-indol-3-yl)propan-2-ol (209 mg, 1 mmole) were dissolvedin conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowlyadded dropwise to this mixture. After a reaction time of 60 min, a redsolution formed. It was stirred at RT for 20 hours. For working up, themixture was diluted with water (20 ml), brought to pH 11 with 5 M NaOHand extracted with MC (3×20 ml). The organic phase was dried with sodiumsulfate and evaporated. The product consisted almost exclusively of themore polar diastereoisomer of6-chloro-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole(390 g of yellow solid). These 390 mg were suspended in hot ethanol (20ml), and a similarly hot solution of citric acid (385 mg, 2 mmoles) inethanol (10 ml) was added. On cooling to approx. 5° C., the citrate ofthe more polar diastereoisomer of6-chloro-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indoleprecipitated out. It was filtered off with suction and dried (768 mg ofyellow solid, m.p. 155-160° C.

Example 213,9-Dimethyl-1,1-(3-dimethylamino-3-phenylpenta-methylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate

4-Dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmoles) and1-methyl-3-(2-trimethylsilanyloxy-propyl)-1H-indole (622 mg, 2 mmoles)were initially introduced into abs. MC (20 ml) under argon,trifluoromethanesulfonic acid (0.18 ml, 2 mmoles) was added, whilestirring, and the mixture was stirred for 20 hours. For working up, 1 MNaOH (20 ml) was added to the reaction mixture and the mixture wasstirred for 30 min. The organic phase was separated, and the aqueoussolution which remained was extracted with MC (2×30 ml). The combinedorganic phases were washed with water (2×30 ml) and dried over sodiumsulfate. Methanol (50 ml) was added to the residue obtained after thesolvent had been distilled off, and the mixture was stirred for 1 hours.The solid which was insoluble in methanol was separated and dried. Oneof the two possible diastereoisomers of3,9-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this manner (560 mg, m.p. 210-212° C.). 388 mg of thiswere dissolved in hot ethanol (50 ml), and a similarly hot solution ofcitric acid (384 mg, 2 mmoles) in ethanol (20 ml) was added. Thesolution was cooled and concentrated to dryness in vacuo. The residueobtained was taken up in water (20 ml), the citrate being obtained as acrystalline solid after trituration. To bring the precipitation tocompletion, the aqueous solution was left to stand overnight. Afterfiltration and drying, 285 mg of the citrate of3,9-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolewere obtained (m.p. 156-158° C.).

Example 221,1-(3-Dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Dimethylamino-4-(4-fluorophenyl)cyclohexanone (705 mg, 3 mmoles) andtryptophol (483 mg, 3 mmoles) were initially introduced into abs. MC (20ml) under argon. Trifluoromethanesulfonic acid trimethylsilyl ester (0.6ml, 3.1 mmoles) was then added very rapidly. The mixture was stirred atroom temperature for 18 hours. For working up, 1 M NaOH (20 ml) wasadded to the reaction mixture and the mixture was stirred for 30 min.The organic phase was separated, and the aqueous phase which remainedwas extracted with MC (3×30 ml). The combined organic phases were washedwith water (2×30 ml) and dried over sodium sulfate. Methanol (20 ml) wasadded to the solid residue obtained after the solvent had been distilledoff, and the mixture was heated, and stirred for 15 hours. The solidcontained in the suspension was filtered out with suction. One of thetwo possible diastereoisomers of1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this manner (755 mg, m.p. 292-302° C.). These 755 mgwere dissolved in hot ethanol (400 ml), and a similarly hot solution ofcitric acid (600 mg, 3.12 mmoles) in ethanol (50 ml) was added. Aftercooling to approx. 5° C., the mixture was left to stand for 2 hours. Theresulting solid was filtered out with suction. The hemicitrate of1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained (632 mg of white solid, m.p. 241-250° C. withdecomposition).

Example 231,1-(3-Dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Dimethylamino-4-(3-fluorophenyl)cyclohexanone (434 mg, 1.84 mmoles)and tryptophol (296 mg, 1.84 mmoles) were initially introduced into abs.MC (20 ml) under argon. Trifluoromethanesulfonic acid trimethylsilylester (0.38 ml, 1.97 mmoles) was then added very rapidly. The mixturewas stirred at room temperature for 20 hours. For working up, 1 M NaOH(20 ml) was added to the reaction mixture and the mixture was stirredfor 30 min. The organic phase was separated, and the aqueous phase whichremained was extracted with MC (3×100 ml). The combined organic phaseswere washed with water (2×30 ml) and dried over sodium sulfate. Methanol(20 ml) was added to the solid residue obtained after the solvent hadbeen distilled off, and the mixture was heated, and stirred for 15 h.The solid contained in the suspension was filtered out with suction. Oneof the two possible diastereoisomers was obtained in this manner (482mg, m.p. 298-301° C.). These 482 mg were dissolved in hot ethanol (400ml), and a similarly hot solution of citric acid (490 mg, 2.55 mmoles)in ethanol (50 ml) was added. After cooling to approx. 5° C., themixture was left to stand for 2 hours. The resulting solid was filteredout with suction. The hemicitrate of1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained (351 mg of white solid, m.p. 286-291° C., from 245 crystalconversion, above 280° C. sublimation).

Example 241,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate, more non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 537 mg, 3mmoles) were initially introduced into abs. MC (20 ml) under argon.

Trifluoromethanesulfonic acid trimethylsilyl ester (0.6 ml, 3.1 mmoles)was then added very rapidly. The mixture was stirred at RT for 20 h. Forworking up, 1 M NaOH (30 ml) was added to the reaction mixture and themixture was stirred for 30 min. The organic phase was separated, and theaqueous phase which remained was extracted with MC (3×60 ml). Thecombined organic phases were washed with water (2×30 ml) and dried oversodium sulfate. Methanol (30 ml) was added to the solid residue obtainedafter the solvent had been distilled off, and the mixture was heated,and stirred for 15 hours. The solid contained in the suspension wasfiltered off with suction and dried. 955 mg of the more non-polardiastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indolewere obtained (m.p. 284-292° C.). 850 mg of this were dissolved in hotethanol (900 ml), and a similarly hot solution of citric acid (1 g, 5.2mmoles) in ethanol (20 ml) was added. After approx. 15 minutes, crystalsprecipitated out at the boiling point. After cooling to approx. 5° C.,the mixture was left to stand for 2 h. The solid formed was filtered offwith suction. 640 mg of the hemicitrate were obtained as a white solid(m.p. 258-282° C.).

Example 251,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate, more polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and2-(5-fluoro-1H-indol-3-yl)-ethanol (“5-fluorotryptophol”, 179 mg, 1mmole) were dissolved in conc. acetic acid (4 ml). Phosphoric acid (1ml, 85 wt. %) was slowly added dropwise to this mixture. The mixture wasstirred at RT for 16 h. For working up, the mixture was diluted withwater (20 ml), brought to pH 11 with 5 M NaOH and extracted with MC(3×20 ml). The combined organic phases were dried with sodium sulfateand evaporated. The residue (364 mg of white solid) was suspended in hotethanol (20 ml), and a similarly hot solution of citric acid (185 mg,0.96 mmole) in ethanol (5 ml) was added. The residue thereby dissolvedcompletely and no longer precipitated out even on cooling to approx. 5°C. Ethanol was removed on a rotary evaporator and the hemicitrate of themore polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this way in a yield of 548 mg as a white solid (m.p.148-155° C.).

Example 261,1-(3-Dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Dimethylamino-4-phenylcyclohexanone (325 mg, 1.5 mmoles) and2-(5-methyl-1H-indol-3-yl)-ethanol (“5-methyltryptophol”, 262 mg, 1.5mmoles) were initially introduced into abs. MC (10 ml) under argon.Trifluoromethanesulfonic acid trimethylsilyl ester (0.3 ml, 1.55 mmoles)was then added very rapidly. The mixture was stirred at room temperaturefor 24 hours. For working up, 1 M NaOH (20 ml) was added to the reactionmixture and the mixture was stirred for 30 min. The organic phase wasseparated, and the aqueous phase which remained was extracted with MC(3×20 ml). The combined organic phases were washed with water (2×30 ml)and dried over sodium sulfate. Methanol (30 ml) was added to the solidresidue obtained after the solvent had been distilled off, and themixture was heated, and stirred for 15 hours. The suspended solid wasfiltered out with suction. One of the two possible diastereoisomers of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained (430 mg, m.p. 259-270° C.). 350 mg of this were dissolvedin hot ethanol (300 ml), and a similarly hot solution of citric acid(300 mg, 1.56 mmoles) in ethanol (10 ml) was added. After approx. 15minutes, crystals precipitated out at the boiling point. After coolingto approx. 5° C., the mixture was left to stand for 2 hours. Theresulting solid was filtered out with suction. It was possible to obtainthe hemicitrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolein this way in a yield of 380 mg (white solid, m.p. 243-265° C.).

Example 271,1-(3-Dimethylamino-3-phenylpentamethylene)-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate

4-Dimethylamino-4-phenylcyclohexanone (325 mg, 1.5 mmoles) and2-(1-phenyl-1H-indol-3-yl)-ethanol (355 mg, 1.5 mmoles) were initiallyintroduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonicacid (0.14 ml, 1.58 mmoles) was then added very rapidly. The mixture wasstirred at RT for 20 h. For working up, 1 M NaOH (30 ml) was added tothe reaction mixture and the mixture was stirred for 30 min. The organicphase was separated, and the aqueous phase which remained was extractedwith MC (3×60 ml). The combined organic phases were washed with water(2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added tothe solid residue obtained after the solvent had been distilled off, andthe mixture was heated, and stirred for 15 hours. The suspended solidwas filtered out with suction. One of the two possible diastereoisomersof1,1-(3-dimethylamino-3-phenylpentamethylene)-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained (385 mg, m.p. 256-261° C.). 672 mg of this diastereoisomerof1,1-(3-dimethylamino-3-phenylpenta-methylene)-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indolewere dissolved in hot ethanol (500 ml), and a similarly hot solution ofcitric acid (500 g, 2.6 mmoles) in ethanol (20 ml) was added. Thesolution was then concentrated to approx. 100 ml. After cooling toapprox. 5° C., the mixture was left to stand for 48 hours. The resultingsolid was filtered out with suction and dried. 570 mg of the citrate of1,1-(3-dimethylamino-3-phenylpenta-methylene)-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indolewere obtained (white solid, m.p. 255-260° C., from 205° C. crystalconversion).

Example 281,1-(3-Methylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Methylamino-4-phenyl-cyclohexanone (609 mg, 3 mmoles) and tryptophol(483 mg, 3 mmoles) were initially introduced into abs. MC (20 ml) underargon. Trifluoromethanesulfonic acid (0.28 ml, 3.16 mmoles) was thenadded very rapidly. The mixture was stirred at room temperature for 20hours. For working up, 1 M NaOH (20 ml) was added to the reactionmixture, and the mixture was stirred for 30 min. The organic phase wasseparated, and the aqueous phase which remained was extracted with MC(3×30 ml). The combined organic extracts were washed with water (2×30ml) and dried over sodium sulfate. Methanol (30 ml) was added to thesolid residue obtained after the solvent had been distilled off, and themixture was heated, and stirred for 15 hours. The solid contained in thesuspension was filtered out with suction. One of the two possiblediastereoisomers of1,1-(3-methylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this manner in a yield of 630 mg (m.p. 260-262° C.). 600mg of this were dissolved in hot ethanol (150 ml), and a similarly hotsolution of citric acid (600 mg, 3.12 mmoles) in ethanol (10 ml) wasadded. After cooling to approx. 5° C., the mixture was left to stand for12 hours. The resulting solid was filtered out with suction. 663 mg ofthe hemicitrate of1,1-(3-methylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-pyrano[3,4-b]indolewere obtained (white solid, m.p. 252-254° C.).

Example 291,1-(3-Dimethylamino-3-phenylpentamethylene)-6-methyl-3,4-dihydro-1H-2,9-diazafluorenecitrate

4-Dimethylamino-4-phenylcyclohexanone (1.2 g, 5.53 mmoles) and5-methyltryptamine (963 mg, 5.53 mmoles) were dissolved in dry methanol(40 ml) with exclusion of oxygen. Sodium sulfate (2 g) was added to thismixture. After a reaction time of 24 hours, the methanol was distilledoff, and the residue was suspended in 1,2-dichloroethane (40 ml).Trifluoroacetic acid (4 ml) was added to the reaction mixture and themixture was stirred at room temperature for 18 hours. For working up,the mixture was diluted with water (30 ml), adjusted to pH 11 with NaOH(5 mole/l) and extracted with 1,2-dichloroethane (3×30 ml). The organicphase was dried with sodium sulfate and concentrated. The brown solidresidue was recrystallized from methanol. 236 mg of a white solid wereobtained. 100 mg of this were dissolved in hot ethanol (10 ml), and asimilarly hot solution of citric acid (62 mg, 0.32 mmole) in ethanol (1ml) was added. After cooling to approx. 5° C., the mixture was left tostand for 4 hours. The resulting solid was filtered out with suction.The citrate of a diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 150 mg (as a white solid, m.p.205-206° C.).

Example 302-Acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-3,4-dihydro-1H-2,9-diazafluorenecitrate

120 mg (0.32 mmole) of the1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-methyl-3,4-dihydro-1H-2,9-diazafluoreneprepared according to Example 29 were dissolved in pyridine (10 ml).Thereafter, acetic anhydride (305 μl, 3.2 mmoles) was added dropwise andthe mixture was stirred at room temperature for 3 days. For working up,the pyridine was concentrated and the mixture was diluted with water (10ml), brought to pH 11 with 5 M NaOH and extracted with EA (3×10 ml). Thecombined organic phases were dried with sodium sulfate and evaporatedand the residue obtained was purified by column chromatography on silicagel with methanol. 120 mg of a white foam were obtained and weredissolved in hot ethanol (10 ml), and a similarly hot solution of citricacid (67 mg, 0.35 mmole) in ethanol (1 ml) was added. After cooling toapprox. 5° C., the mixture was left to stand for 4 hours. The resultingsolid was filtered out with suction. The citrate of2-acetyl-1,1-(3-dimethylamino-3-phenylpenta-methylene)-6-methyl-3,4-dihydro-1H-2,9-diazafluorenewas obtained in a yield of 175 mg (white solid, m.p.: 162-167° C.).

Example 311,1-(3-Dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluorenecitrate, more polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (544 mg, 2.5 mmoles) and6-fluorotryptamine (445 mg, 2.5 mmoles) were dissolved in dry methanol(20 ml). Sodium sulfate (1 g) was added to this mixture. After areaction time of 24 hours, methanol was distilled off and the residuewas suspended in 1,2-dichloroethane (20 ml). Trifluoroacetic acid (2 ml)was added to the reaction mixture and the mixture was stirred at roomtemperature for 18 hours. For working up, the mixture was diluted withwater (20 ml), brought to pH 11 with NaOH (5 mole/l) and extracted with1,2-dichloroethane (3×20 ml). The combined organic phases were driedwith sodium sulfate and concentrated. The solid, white residue wasrecrystallized from methanol, and the more polar diastereoisomer (300 mgof white solid) was obtained from the mother liquor. These 300 mg weredissolved in hot ethanol (20 ml), and a similarly hot solution of citricacid (193 mg, 1 mmole) in ethanol (2 ml) was added. After cooling toapprox. 5° C., the mixture was left to stand for 4 hours. The resultingsolid was filtered out with suction and dried. The citrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 430 mg (white solid, m.p.:224-226° C.).

Example 322-Acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluorenecitrate, more non-polar diastereoisomer

The residue obtained according to Example 31 by recrystallization frommethanol was recrystallized again from EA. 330 mg of the more non-polardiastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluorenewere obtained as a white solid. 150 mg of this were dissolved inpyridine (10 ml). Thereafter, acetic anhydride (380 μl, 4 mmoles) wasadded dropwise and the mixture was stirred at RT for 3 days. For workingup, the mixture was concentrated, diluted with water (10 ml), adjustedto pH 11 with 5 M NaOH and extracted with EA (3×10 ml). The combinedorganic phases were dried with sodium sulfate and evaporated. Theresulting residue was purified by column chromatography on silica gelwith methanol. The 154 mg2-acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluoreneobtained were dissolved in hot ethanol (10 ml), and a similarly hotsolution of citric acid (87 mg, 0.45 mmole) in ethanol (1 ml) was added.After cooling to approx. 5° C., the mixture was left to stand for 4hours. The resulting solid was filtered out with suction. The citrate ofthe more non-polar diastereoisomer of2-acetyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-7-fluoro-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 230 mg (white solid, m.p.135-140° C.).

Example 331,1-(3-Dimethylamino-3-phenylpentamethylene)-3-methyl-3,4-dihydro-1H-2,9-diazafluorenecitrate

4-Dimethylamino-4-phenylcyclohexanone (435 mg, 2 mmoles) and rac.2-(1H-indol-3-yl)-1-methylethylamine (“DL-α-methyltryptamine”, 348 mg, 2mmoles) were dissolved in dry methanol (20 ml). Sodium sulfate (1 g) wasadded to this mixture. After a reaction time of 24 hours, methanol wasdistilled off, and the residue was suspended in 1,2-dichloroethane (20ml). Trifluoroacetic acid (2 ml) was added to the reaction mixture andthe mixture was stirred at room temperature for 16 hours. For workingup, the mixture was diluted with water (20 ml), adjusted to pH 11 withNaOH (5 mole/l) and extracted with 1,2-dichloroethane (3×20 ml). Theorganic phase was dried with sodium sulfate and concentrated. Theresidue was a contaminated mixture of the two diastereoisomeric1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-3,4-dihydro-1H-2,9-diazafluorenes,which it was possible to purify by recrystallization from methanol butnot to separate (660 mg of white solid). 200 mg of this were dissolvedin hot ethanol (15 ml), and a similarly hot solution of citric acid (124mg, 0.64 mmole) in ethanol (2 ml) was added. After cooling to approx. 5°C., the mixture was left to stand for 3 hours. The resulting solid wasfiltered out with suction and dried. The citrate of1,1-(3-dimethylamino-3-phenyl-pentamethylene)-3-methyl-3,4-dihydro-1H-2,9-diazafluorenewas obtained in this way in a yield of 140 mg (white solid, m.p.209-212° C.). Only one of the two diastereoisomers was obtained in thiscitrate precipitation.

Example 341,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-3,4-dihydro-1H-2,9-diazafluorenedihydrochloride

4-Dimethylamino-4-phenylcyclohexanone (1.01 g, 4.64 mmoles) and5-fluorotryptamine (827 mg, 4.64 mmoles) were dissolved in dry methanol(40 ml). Sodium sulfate (2 g) was added to this mixture. After areaction time of 24 hours, methanol was distilled off and the residuewas suspended in 1,2-dichloroethane (40 ml). Trifluoroacetic acid (4 ml)was added to the reaction mixture, and the mixture was stirred at roomtemperature for 16 hours. For working up, the mixture was diluted withwater (40 ml), adjusted to pH 11 with NaOH (5 mole/l) and extracted with1,2-dichloroethane (3×25 ml). The combined organic phases were driedwith sodium sulfate and concentrated. The brown solid residue obtainedwas recrystallized from methanol, the mixture of more polar and morenon-polar diastereoisomer of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3,4-dihydro-1H-2,9-diazafluoreneobtained (110 mg of white solid) was dissolved in 2-butanone (3 ml), andchlorotrimethylsilane (97 μl, 0.73 mmole) was added. The resulting solidwas filtered out with suction and dried. The dihydrochloride of1,1-(3-dimethylamino-3-phenylpentamethyl-ene)-6-fluoro-3,4-dihydro-1H-2,9-diazafluoreneobtained (131 mg of white solid, m.p. 228-232° C.) was a 60:40 mixtureof the two diastereoisomers.

Example 351,1-(3-Dimethylamino-3-phenylpentamethylene)-6-fluoro-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and1-(5-fluoro-1H-indol-3-yl)-propan-2-ol (579 mg, 3 mmoles) were initiallyintroduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonicacid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added veryrapidly. The mixture was stirred at room temperature for 20 hours. Forworking up, 1 M NaOH (20 ml) was added to the reaction mixture and themixture was stirred for 30 min. The organic phase was separated, and theaqueous phase which remained was extracted with MC (3×30 ml). Thecombined organic phases were washed with water (2×30 ml) and dried oversodium sulfate. Methanol (25 ml) was added to the solid residue obtainedafter the solvent had been distilled off, and the mixture was heated,and stirred for 15 h. The solid which was insoluble in methanol wasfiltered out with suction. One of the two diastereoisomers of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this manner in a yield of 856 mg (m.p. 232-236° C.). 800mg of this were dissolved in hot ethanol (200 ml), and a similarly hotsolution of citric acid (600 mg, 3.12 mmoles) in ethanol (20 ml) wasadded. After cooling to approx. 5° C., no crystal formation was to beobserved. The solution was concentrated in vacuo. Water (30 ml) wasadded to the residue. After trituration, a precipitate precipitated outand, after complete crystallization, was filtered off with suction(hemicitrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole,807 mg of white solid, m.p. 180-182° C.).

Example 363,6-Dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate, more non-polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (651 mg, 3 mmoles) and1-(5-methyl-1H-indol-3-yl)-propan-2-ol (567 mg, 3 mmoles) were initiallyintroduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonicacid trimethylsilyl ester (0.6 ml, 3.1 mmoles) was then added veryrapidly. The mixture was stirred at RT for 20 h. For working up, 1 MNaOH (30 ml) was added to the reaction mixture and the mixture wasstirred for 30 min. The organic phase was separated, and the aqueousphase which remained was extracted with MC (3×30 ml). The combinedorganic phases were washed with water (2×30 ml) and dried over sodiumsulfate. Methanol (30 ml) was added to the solid residue obtained afterthe solvent had been distilled off, and the mixture was heated, andstirred for 15 hours. The more non-polar of the two possible racemicdiastereoisomers of3,6-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole(840 mg, m.p. 292-296° C.) was obtained by filtering out the solid whichwas insoluble in methanol. 600 mg of this were dissolved in hot ethanol(300 ml), and a similarly hot solution of citric acid (400 mg, 2.08mmoles) in ethanol (20 ml) was added. A solid already started toprecipitate out at the boiling point. To bring the crystallization tocompletion, the solution was left at approx. 5° C. for 15 hours. Theprecipitate was then separated and dried. It was possible to obtain thehemicitrate of the more non-polar diastereoisomer of3,6-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolein this way in a yield of 630 mg (white solid, m.p. 258-276° C.).

Example 373,6-Dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate, more polar diastereoisomer

4-Dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) and1-(5-methyl-1H-indol-3-yl)-propan-2-ol (189 mg, 1 mmole) were dissolvedin conc. acetic acid (4 ml). Phosphoric acid (1 ml, 85 wt. %) was slowlyadded dropwise to this mixture. After a reaction time of 60 min, a redsolution formed. It was stirred at room temperature for 20 hours. Forworking up, the mixture was diluted with water (20 ml), adjusted to pH11 with 5 M NaOH and extracted with MC (3×20 ml). The organic phase wasdried with sodium sulfate and evaporated to dryness. The residue (370 mgof white solid) was suspended in hot ethanol (20 ml), and a similarlyhot solution of citric acid (385 mg, 2 mmoles) in ethanol (10 ml) wasadded. The residue thereby dissolved completely, but precipitated outagain on cooling to approx. 5° C. The citrate of the more polardiastereoisomer of3,6-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indolewas filtered out with suction and dried (690 mg of white solid, m.p.162-168° C.).

Example 381,1-(3-Dimethylamino-3-phenylpentamethylene)-3-methyl-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indolecitrate

4-Dimethylamino-4-phenylcyclohexanone (435 mg, 2 mmoles) and2-(1-phenyl-1H-indol-3-yl)-ethanol (503 mg, 2 mmoles) were dissolved inconc. acetic acid (8 ml). Phosphoric acid (2 ml, 85 wt. %) was slowlyadded dropwise to this mixture. After a reaction time of 30 min, a redsolution formed. It was stirred at room temperature for 20 hours. Forworking up, the mixture was diluted with water (40 ml), brought to pH 11with 5 M NaOH and extracted with MC (3×30 ml). The organic phase wasdried with sodium sulfate and evaporated to dryness. The residuecontained only one of the two possible racemic diastereoisomers of thetarget product, which it was possible to obtain in a yield of 900 mg asa white solid. These 900 mg were suspended in hot ethanol (50 ml), and asimilarly hot solution of citric acid (770 mg, 4 mmoles) in ethanol (15ml) was added. The solid which had precipitated out on cooling toapprox. 5° C. was filtered out with suction and dried. It was possibleto obtain the citrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indolein this way in a yield of 1.2 g as a white solid (m.p. 253-256° C.).

Example 391,1-(3-Dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenemethanesulfonate

4-Dimethylamino-4-(4-fluorophenyl)cyclohexanone (353 mg, 1.5 mmoles) and2-(1H-indol-3-yl)ethanethiol (266 mg, 1.5 mmoles) were initiallyintroduced into abs. MC (10 ml) under argon. Methanesulfonic acidtrimethylsilyl ester (254 μl, 1.65 mmoles) was then added. After themixture had been stirred at room temperature for 20 hours, noprecipitate was visible. Methanesulfonic acid trimethylsilyl ester (254μl, 1.65 mmole) was again added to the reaction mixture. Thereafter, themixture was stirred for 3 days at room temperature. For working up, themethane-sulfonate which had precipitated out was filtered out withsuction and washed with MC (3×1 ml) and diethyl ether (3×3 ml). Themethane-sulfonate of one of the two possible diastereoisomers of1,1-(3-dimethyl-amino-3-(4-fluorophenyl)penta-methylene)-1,3,4,9-tetrahydro-2-thia-9-aza-fluorenewas obtained in a yield of 550 mg as a white solid (m.p. 245-250° C.).

Example 401,1-(3-Dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenemethanesulfonate

4-Dimethylamino-4-(3-fluorophenyl)cyclohexanone (353 mg, 1.5 mmoles) and2-(1H-indol-3-yl)ethanethiol (266 mg, 1.5 mmoles) were initiallyintroduced into abs. MC (10 ml) under argon. Methanesulfonic acid (195μl, 3 mmoles) was then added. After the reaction mixture had beenstirred at room temperature for 2 hours, it was a clear solution. Afterstirring at room temperature for a further 16 hours, a copious whiteprecipitate had precipitated out. The suspension was diluted with MC (5ml). The precipitate was filtered out with suction, washed with MC (3×1ml) and dried. The methanesulfonate of one of the two possiblediastereoisomers of1,1-(3-dimethylamino-3-(3-fluorophenyl)penta-methylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorenewas obtained as a cream-colored solid (695 mg, m.p. 258-260° C.).

Example 411,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-9-oxa-2-thiafluorenecitrate

4-Dimethylamino-4-phenylcyclohexanone (2.06 g, 9.5 mmoles) and2-(benzofuran-3-yl)ethanethiol (1.70 g, crude product, according to NMRcontains approx. 80% of the desired thiol) were initially introducedinto abs. MC (25 ml) under argon. Methanesulfonic acid (680 μl, 10.45mmoles) was then added. The mixture was stirred at room temperature for4 days. For working up, water (15 ml) was added to the mixture. Theaqueous phase was separated and extracted with MC (3×20 ml). Thecombined organic phases were washed with 2 M sulfuric acid andconcentrated. The tacky, yellow residue was washed with diethyl ether(3×10 ml), and 2 M NaOH (20 ml) was then added. The resulting mixturewas extracted with diethyl ether (3×15 ml). The ether phase was driedover sodium sulfate and concentrated. One of the two possiblediastereoisomers of the target product was isolated from the resultingresidue by column chromatography on silica gel with EA/ethanol in avolume ratio of 9:1 (112 mg of white solid, m.p. 160-165° C.). These 112mg were dissolved in boiling ethanol (12 ml), an ethanolic solution (2ml) of citric acid (62 mg, 0.324 mmole) was added and the mixture wasstirred for 10 min. After cooling, the solvent was concentrated toapprox. 5 ml and brought to approx. 5° C. The white precipitate whichhad precipitated out after approx. 6 hours was separated and dried. 112mg of the citrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-9-oxa-2-thiafluorenewere obtained (white solid, m.p. 207-209° C.).

Example 421,1-(3-Dimethylamino-3-phenylpentamethylene)-1,2,3,4-tetrahydrobenzo[4,5]furo[2,3-c]pyridinecitrate

2-(Benzofuran-3-yl)ethylamine (0.74 g, 4.6 mmoles) and4-dimethylamino-4-phenylcyclohexanone (1.01 mg, 4.6 mmoles) weredissolved in methanol (35 ml) and the solution was stirred at roomtemperature for 24 hours. Thereafter, the mixture was evaporated todryness. The residue was suspended in dry 1,2-dichloroethane (40 ml),and trifluoroacetic acid (4 ml) was added. The mixture was stirred atroom temperature for 24 hours. For working up, the pH was adjusted to 11with 5 M NaOH. After subsequent addition of EA (20 ml), adiastereoisomer of the target product precipitated out as a whiteprecipitate. After 15 min, the precipitate was filtered out with suctionand dried (867 mg, m.p. 193-196° C.). 400 mg of this were dissolved inhot ethanol (9 ml), and a similarly hot ethanolic solution of citricacid (212 mg, 1.1 mmol in 3 ml ethanol) was added. A white precipitatethereby precipitated out immediately. To bring the precipitation tocompletion, the mixture was left at approx. 5° C. for 4 hours. Theresulting solid was filtered out with suction. The citrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-1,2,3,4-tetrahydrobenzo-[4,5]furo[2,3-c]pyridinewas obtained in this way in a yield of 400 mg (white solid, m.p.222-224° C.).

Example 436,6-(3-Dimethylamino-3-phenylpentamethylene)-1,2,3,4,4a,6,7,11c-octahydro-5-oxa-7-azabenzo[c]fluorenecitrate

4-Dimethylamino-4-phenylcyclohexanone (261 mg, 1.2 mmoles) and rac.2-(1H-indol-3-yl)-cyclohexanol (260 mg, 1.2 mmoles) were initiallyintroduced into abs. MC (20 ml) under argon. Trifluoromethanesulfonicacid trimethylsilyl ester (0.25 ml, 1.3 mmoles) was then added rapidly.The mixture was stirred at room temperature for 20 hours. For workingup, 1 M NaOH (20 ml) was added to the reaction mixture, and the mixturewas stirred for 30 min. The organic phase was separated, and the aqueousphase which remained was extracted with MC (3×30 ml). The combinedorganic phases were washed with water (2×30 ml), dried over sodiumsulfate and concentrated to dryness. According to NMR, the solid formedfrom the residue after addition of methanol (approx. 25 ml) consisted ofthe two diastereoisomeric target products to be expected. To bring theprecipitation to completion, the mixture was cooled to approx. 5° C. for2 hours. The solid was then filtered out with suction and dried. Thediastereoisomer mixture of the target product was obtained in thismanner in a yield of 277 mg with a melting point of 150-170° C. 250 mgof this were dissolved in hot ethanol (200 ml), and a similarly hotsolution of citric acid (192 mg, 1 mmole) in ethanol (20 ml) was added.No crystal formation was to be observed even after cooling the reactionmixture to approx. 5° C. The solution was therefore concentrated invacuo to approx. 30 ml and left at approx. 5° C. for 3 days. 190 mg ofthe citrate of an approx. 60:40 mixture of the two diastereoisomeric6,6-(3-dimethylamino-3-phenylpentamethylene)-1,2,3,4,4a,6,7,11c-octahydro-5-oxa-7-azabenzo[c]fluoreneswere obtained (white solid, m.p. 184-192° C.).

Example 441,1-(3-Dimethylamino-3-phenylpentamethylene)-6-bromo-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Dimethylamino-4-phenylcyclohexanone (326 mg, 1.5 mmoles) and5-bromo-3-(2-trimethylsilanyloxy-ethyl)-1H-indole (468 mg, 1.5 mmoles)were initially introduced into MC (50 ml). Trifluoromethanesulfonic acid(0.145 ml, 1.51 mmoles) was then added rapidly. The mixture was stirredat room temperature for 15 hours. For working up, 2 M NaOH (10 ml) wasadded to the reaction mixture, and the mixture was stirred for 30 min.The organic phase was separated, and the aqueous phase was extractedwith MC (3×30 ml). The combined organic phases were washed with water(2×30 ml) and dried over sodium sulfate. Methanol (30 ml) was added tothe solid residue obtained after the solvent had been distilled off, andthe mixture was heated, and stirred at room temperature for 15 hours.The solid suspended in methanol was filtered out with suction. One ofthe two possible diastereoisomers of the target product was obtained inthis way in a yield of 583 mg (m.p. 271-281° C.). 550 mg of this weredissolved in hot ethanol (300 ml), and a similarly hot ethanolic citricacid solution (385 mg, 2 mmol in 20 ml) was added. A crystalline solidalready precipitated out at the boiling point. To bring thecrystallization to completion, the mixture was left at 5° C. for 12hours. The solid formed was filtered off with suction. The hemicitrateof1,1-(3-dimethylamino-3-phenylpentamethylene)-6-bromo-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this way in a yield of 510 mg (white solid, m.p.262-267° C.).

Example 451,1-(3-Dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indol-6-olcitrate

4-Dimethylamino-4-phenylcyclohexanone (490 mg, 2.26 mmoles) and3-(2-hydroxyethyl)-1H-indol-5-ol (400 mg, 2.26 mmoles) were initiallyintroduced into MC (150 ml). Trifluoromethanesulfonic acidtrimethylsilyl ester (0.45 ml, 2.3 mmoles) was then added rapidly. Themixture was stirred at room temperature for 3 days. For working up, 1 MNaOH (30 ml) was added to the reaction mixture and the mixture wasstirred for 30 min. The mixture was filtered, the organic phase wasseparated, and the aqueous phase which remained was extracted with MC(3×60 ml). The combined organic phases were washed with water (2×30 ml)and dried over sodium sulfate. Methanol (50 ml) was added to the solidresidue obtained after the solvent had been distilled off. The clearsolution formed was concentrated to approx. 10 ml and left to stand at5° C. for 2 hours. The solid which had precipitated from methanol wasfiltered out with suction. One of the two diastereoisomeric targetproducts was obtained (180 mg, m.p. 252-257° C.). 160 mg of this weredissolved in hot ethanol (20 ml), and a similarly hot ethanolic citricacid solution (150 mg, 0.78 mmol in 10 ml) was added. A crystallinesolid already precipitated out at the boiling point. To bring thecrystallization to completion, the mixture was left at 5° C. for 20hours. The resulting solid was filtered out with suction. The citrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano-[3,4-b]indol-6-olwas obtained in this way in a yield of 125 mg (white solid, m.p.248-254° C.).

Example 46(3S)-1,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-3-methoxycarbonyl-1H-2,9-diazafluorenecitrate

4-Dimethylamino-4-phenylcyclohexanone (434.8 mg, 2 mmoles) andL-tryptophan methyl ester ((2S)-2-amino-3-(1H-indol-3-yl)propionic acidmethyl ester, 436.5 mg, 2 mmoles) were dissolved in dry methanol (20ml). After a reaction time of 24 hours, the methanol was distilled offand the yellow, oily residue was suspended in 1,2-dichloroethane (20ml).

Trifluoroacetic acid (2 ml) was added to the reaction mixture and themixture was stirred at room temperature for 18 hours. For working up,the mixture was diluted with water (20 ml) and adjusted to pH 11 withNaOH (5 mole/l). After addition of EA (20 ml), a white solidprecipitated out, and was filtered out with suction. The solid waswashed with water (3×5 ml) and dried. It was a mixture of thediastereoisomers of the target product (70% non-polar:30% polar) whichit was possible to obtain as a white solid in a yield of 600 mg. These600 mg were dissolved in hot ethanol (30 ml), and a similarly hotsolution of citric acid (276 mg, 1.44 mmoles) in ethanol (5 ml) wasadded. After cooling to approx. 5° C., the mixture was left to stand for4 hours. The resulting solid was filtered out with suction. It waspossible to obtain the citrate of(3S)-1,1-(3-dimethylamino-3-phenylpenta-methylene)-3,4-dihydro-3-methoxycarbonyl-1H-2,9-diazafluorenein this way as an approx. 70:30 mixture of the more non-polar and morepolar diastereoisomer in a yield of 875 mg (white solid, m.p. 193-196°C.).

Example 47(3S)-1,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene-3-methanolcitrate

4-Dimethylamino-4-phenylcyclohexanone (434.8 mg, 2 mmoles) andL-tryptophanol ((2S)-2-amino-3-(1H-indol-3-yl)-propan-1-ol, 380.5 mg, 2mmoles) were dissolved in dry methanol (20 ml). After a reaction time of24 hours, methanol was distilled off and the yellow, oily residue wassuspended in 1,2-dichloroethane (20 ml). Trifluoroacetic acid (2 ml) wasadded to the reaction mixture and the mixture was stirred at roomtemperature for 18 hours. For working up, the mixture was diluted withwater (20 ml) and adjusted to pH 11 with NaOH (5 mole/l). After additionof EA (20 ml), a white solid precipitated out, and was filtered out withsuction. The solid was washed with water (3×5 ml) and dried. It was amixture of the diastereoisomers of the target product (30% non-polar:70%polar), which it was possible to obtain as a white solid with a yield of700 mg. These 700 mg were dissolved in hot ethanol (40 ml), and asimilarly hot solution of citric acid (346 mg, 1.8 mmoles) in ethanol (5ml) was added. After cooling to approx. 5° C., the mixture was left tostand for 4 hours. The resulting solid was filtered out with suction. Itwas possible to obtain the citrate of(3S)-1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene-3-methanolin this way in a yield of 1.0 g as an approx. 30:70 mixture of the morenon-polar and more polar diastereoisomer (white solid, m.p. 265-270°C.).

Example 481,1-(3-Dimethylamino-3-phenylethyl-pentamethylene)-3,4-dihydro-1H-2,9-diazafluorene

4-Dimethylamino-4-phenethyl-cyclohexanone (5 g, 20 mmoles) andtryptamine (3.2 g, 20 mmoles) were dissolved in dry methanol (200 ml).After a reaction time of 24 hours, methanol was distilled off and theyellow, oily residue was suspended in 1,2-dichloroethane (200 ml).Trifluoroacetic acid (20 ml) was added to the reaction mixture and themixture was stirred at room temperature for 2 hours. For working up, themixture was diluted with water (100 ml) and adjusted to pH 11 with NaOH(5 mole/l). After addition of EA (50 ml), a white solid precipitated andwas filtered out with suction. The solid was washed with water (3×25 ml)and dried over sodium sulfate. It was a mixture of the diastereoisomersof the target product (10% non-polar:90% polar), which was obtained as awhite solid (m.p. 225-230° C.) in a yield of 4.42 g.

Example 491,1-(3-Methylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indolehemicitrate

4-Methylamino-4-phenyl-cyclohexanone (406 mg, 2 mmoles) and5-fluoro-3-(2-trimethylsilanyloxyethyl)-1H-indole (503 mg, 2 mmoles)were initially introduced into MC (50 ml). Trifluoromethanesulfonic acid(0.18 ml, 2.03 mmoles) was then added rapidly. The mixture was stirredat room temperature for 20 hours. For working up, 2 M NaOH (20 ml) wasadded to the reaction mixture, and the mixture was stirred for 20 min.The organic phase was separated, and the aqueous phase which remainedwas extracted with MC (3×30 ml). The combined organic phases were washedwith water (2×30 ml) and dried over sodium sulfate. Methanol (25 ml) wasadded to the solid residue obtained after the solvent had been distilledoff, and the mixture was heated, and then stirred at room temperaturefor 4 hours. The solid suspended in methanol was filtered out withsuction. One of the two possible diastereoisomers of the target productwas obtained in this manner in a yield of 490 mg (m.p. 248-252° C.). 450mg of this were dissolved in hot ethanol (50 ml), and a similarly hotethanolic citric acid solution (384 mg, 2 mmol in 10 ml) was added. Acrystalline solid already precipitated out at the boiling point. Tobring the crystallization to completion, the mixture was left at approx.5° C. for 15 hours. The resulting solid was filtered out with suction.The hemicitrate of1,1-(3-methylamino-3-phenylpenta-methylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indolewas obtained in this way in a yield of 550 mg (white solid, m.p.226-228° C.).

Example 501,1-(3-Dimethylamino-3-(4-fluorophenyl)pentamethylene)-3,4-dihydro-1H-2,9-dithiafluorenemethanesulfonate

4-Dimethylamino-4-(4-fluorophenyl)cyclohexanone (353 mg, 1.5 mmoles) and2-(benzo[b]thiophen-3-yl)ethanethiol (297 mg in 11.5 ml of solution, 1.5mmoles) were initially introduced into absolute MC (20 ml) under argon.Methanesulfonic acid (194.5 μl, 3.0 mmoles) was then added. The mixturewas stirred at room temperature for 24 hours. A further 100 μlmethanesulfonic acid were added to the reaction mixture and the mixturewas stirred again at room temperature for 20 hours. For working up,water (4 ml) was added to the clear reaction mixture, and the mixturewas stirred for 1 hour. A precipitate thereby precipitated out. Theprecipitate was filtered out with suction, washed with water (2×1 ml)and diethyl ether (2×2 ml) and dried. The white solid was themethanesulfonate of1,1-(3-dimethylamino-3-(4-fluorophenyl)penta-methylene)-3,4-dihydro-1H-2,9-dithiafluorene(262 mg, m.p. 256-258° C.).

Example 511,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dithiafluorenecitrate

4-Dimethylamino-4-phenethyl-cyclohexanone (326 mg, 1.5 mmoles) togetherwith 2-(benzo[b]thiophen-3-yl)ethanethiol (297 mg, 1.5 mmoles) wereinitially introduced into absolute methylene chloride (20 ml) underargon, and methanesulfonic acid (195 μl, 3.0 mmoles) was added. Themixture was stirred at room temperature for 24 hours. A further 100 μlmethanesulfonic acid were added to the reaction mixture, and the mixturewas stirred again at room temperature for 20 hours. For working up,water (5 ml) was added to the clear reaction mixture and the mixture wasstirred for 1 hour. It was then adjusted to pH 11 with 1 M NaOH anddiluted with MC (5 ml). The phases were separated. The aqueous phase wasextracted with MC (3×10 ml). The extracts were combined, washed oncewith saturated NaCl solution and dried over sodium sulfate. After the MChad been distilled off, the residue was a yellow solid. Forpurification, ethanol (5 ml) was added to this and the mixture wasboiled under reflux for 10 min. After cooling to room temperature, themixture was stirred for 24 hours. The precipitate present was filteredout with suction, washed with cold ethanol (3×2 ml) and dried. One ofthe two possible free bases of the target product (335 mg, beige, 57%)was obtained in this way with a melting point of 210-214° C. 120 mg ofthis were dissolved in hot ethanol (40 ml), citric acid (59.2 mg, 0.308mmol, dissolved in 1 ml ethanol) was added, and the mixture was stirredat 65° C. for 10 min. After cooling to room temperature, the mixture wasstirred for 20 hrs. Since no precipitate had precipitated out, theethanol was concentrated down to 2 ml and diethyl ether (30 ml) wasslowly added. The resulting solid was filtered out with suction, washedwith diethyl ether (3×2 ml) and then dried. 152 mg of the citrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dithiafluorenewere obtained as a white solid (m.p. 125-128° C.).

Example 521,1-(3-Dimethylamino-3-phenylpentamethylene)-2-oxo-1,3,4,9-tetrahydro-2-thia-9-azafluorenecitrate

1,1-(3-Dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dithiafluorene(200 mg, 0.53 mmole) was suspended in glacial acetic acid (3 ml), 30percent strength hydrogen peroxide (200 μl) were added dropwise, whilestirring, and the mixture was stirred at room temperature for 2 hours.For working up, 5 ml water were added to the reaction mixture and themixture was rendered alkaline with 5 M NaOH. A suspension therebyformed, which did not dissolve completely even after the addition of EA(50 ml). The precipitate was filtered out with suction, washed withwater (2×1 ml) and discarded. The aqueous mother liquor was brought topH 11 with 5 M NaOH. A white precipitate thereby precipitated out. Thesolid was filtered out with suction, washed with water (1×2 ml) andether (3×1 ml) and dried. 76 mg1,1-(3-dimethylamino-3-phenylpentamethylene)-2-oxo-1,3,4,9-tetrahydro-2-thia-9-azafluorenewere obtained (m.p. 188-192° C.). 61 mg of this were dissolved in hotethanol (8 ml), citric acid (32.8 mg, 0.17 mmole) was added and themixture was stirred at 65° C. for 10 min. After cooling to roomtemperature the mixture was stirred for 20 hours. Because only littlewhite precipitate had precipitated out, the ethanol was concentrateddown to 2 ml and ether (30 ml) was slowly added. The resulting solid wasfiltered out with suction, washed with ether (3×2 ml) and then dried. 74mg of the citrate of1,1-(3-dimethylamino-3-phenylpentamethylene)-2-oxo-1,3,4,9-tetrahydro-2-thia-9-azafluorenewere obtained (white solid, m.p. 162-167° C.).

Example 531,1-(3-Dimethylamino-3-benzylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene

4-Benzyl-4-dimethylaminocyclohexanone (3.47 g, 15 mmole) and tryptamine(2.40 g, 15 mmoles) were dissolved in dry methanol (150 ml) under argon.After a reaction time of 24 hours, methanol was distilled off, and theresidue was suspended in 1,2-dichloroethane (150 ml). Trifluoroaceticacid (15 ml) was added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hours. For working up, water (100 ml)was added to the mixture and the mixture was adjusted to pH 11 with NaOH(5 mole/l). After addition of EA (70 ml), a white solid precipitated outon stirring, and was filtered out with suction over a frit. The solidwas washed with water (5×20 ml) and dried. A diastereoisomer mixture of1,1-(3-dimethylamino-3-benzylpentamethylene)-3,4-dihydro-1H-2,9-diazafluorene(15% non-polar:85% polar) was obtained as a white solid with a meltingpoint of 195-200° C. and a yield of 3.0 g.

Preparation of the Structural Units Used:

Trimethylsilyl ether—General Instructions Based on the Example of3-(2-trimethylsilanyloxyethyl)-1H-indole

Tryptophol (4.83 g, 30 mmoles) was initially introduced into dry THF (80ml), and first hexamethyldisilazane (30 ml, 141 mmoles) and thenchlorotrimethylsilane (8 ml, 62.6 mmoles) were added at roomtemperature. The mixture was stirred at room temperature for 20 hours.The THF was distilled off, and saturated sodium bicarbonate solution wasadded to the residue until a basic reaction was obtained. The aqueoussolution was extracted with ether. The organic phase was washed withwater and dried over sodium sulfate. After removal of the solvent, thetrimethylsilyl ether was obtained in a yield of 6.99 g as a crystallinesolid (m.p. 47-48° C.).

2-(Benzofuran-3-yl)ethanethiol

Triphenylphosphane dibromide (5.52 g, 14.4 mmoles) was suspended in abs.acetonitrile (15 ml) under argon, the suspension was brought to 19° C.in a water-bath and 2-(benzofuran-3-yl)ethanol (2.11 g, 13.1 mmoles) inabs. acetonitrile (7 ml) was added in the course of 15 min. During theaddition the temperature of the reaction mixture was kept between 19 and21° C. The mixture was then left to stand for 12 hours without furthercooling. The reaction mixture was filtered and the filtrate obtained wasconcentrated. The residue obtained was taken up in cyclohexane (20 ml),and the mixture was filtered over a silica gel layer (15 g) about 3 cmthick. The silica gel was washed with cyclohexane (5×20 ml) and thefiltrate obtained was concentrated. 2.47 g 3-(2-bromoethyl)benzofuranwere obtained as a yellowish oil.

Sodium thiosulfate pentahydrate (5.44 g, 21.9 mmoles) was dissolved inwater (22 ml), and the 3-(2-bromoethyl)benzofuran (2.90 g, 12.9 mmoles),dissolved in ethanol (40 ml), was added in the course of 10 min, whilestirring. The reaction mixture was then boiled under reflux for 4 hours.For working up, the ethanol contained in the solvent mixture wasdistilled off in vacuo. The aqueous residue was extracted with diethylether (3×20 ml) and the organic phase was washed with water (2×20 ml).The combined aqueous phases were evaporated on a rotary evaporator. Thewhite-yellowish residue (3.63 g) obtained in this way consists of thesodium salt of thiosulfuric acid S-[2-benzofuran-3-yl)-ethyl]ester(“Bunte salt”) contains an undefined residual amount of water. Thesubsequent conversion to the thiol was carried out without furtherpurification. The resulting 3.63 g of the sodium salt of thiosulfuricacid S-[2-benzofuran-3-yl)ethyl]ester were suspended in 50 wt. %strength phosphoric acid (60 ml) under argon. The reaction mixtureobtained was then covered with a layer of diethyl ether (75 ml) and themixture was heated under reflux (7 hours), with vigorous stirring, untilsolid was no longer to be observed in the aqueous phase. After cooling,the two phases were separated and the aqueous phase was extracted withdiethyl ether (4×15 ml). The combined ethereal phases were washed withwater (2×10 ml) and dried over sodium sulfate. According to NMR, theresidue (yellowish oil, 1.71 g) obtained after removal of the diethylether contained approx. 80% of the desired2-(benzo-furan-3-yl)ethanethiol, which was employed without furtherpurification.

3-(2-Hydroxy-ethyl)-1H-indol-5-ol (5-hydroxy-tryptophol)

5-Hydroxyindol-3-acetic acid (1.91 g, 10 mmoles) was initiallyintroduced into MC (40 ml) under argon, the mixture was cooled to −78°C. and diisopropylaluminium hydride (0.2 M in toluene, 40 ml, 48 mmoles)was added in the course of 20 min, while stirring. When the addition ofthe reducing agent had ended, the mixture was allowed to come to RT inthe course of 5 hours and was then left at RT for a further hour. Forworking up, methanol (2 ml) was cautiously added to the reactionmixture. The previously continuously solid mass became liquid againduring the addition. Saturated NaCl solution (10 ml) was now added inportions to the mixture. The resulting mixture was left to standovernight and then filtered off with suction over kieselguhr. The filtercake was washed with a total of 400 ml MC. The filtrate was dried oversodium sulfate and concentrated. 730 mg3-(2-hydroxy-ethyl)-1H-indol-5-ol were obtained (m.p. 98-102° C.).

Overview of the Examples:

Example No. Structure Salt form Comments 1

hydrochloride more non-polar diastereomer 2

hydrochloride more polar diastereomer 3

hemicitrate more non-polar diastereomer 4

hemicitrate more non-polar diastereomer 5

citrate more polar diastereomer 6

tartrate one of 2 diastereomers 7

triflate one of 2 diastereomers 8

hemicitrate one of 2 diastereomers 9

dihydrochloride 70:30 more non- polar:more polar d. 10

dihydrochloride more polar diastereomer 11

hydrochloride more non-polar diastereomer 12

hydrochloride more polar diastereomer 13

hydrochloride more non-polar diastereomer 14

hemicitrate more non-polar diastereomer 15

citrate more polar diastereomer 16

hemicitrate one of 2 diastereomers 17

citrate more non-polar diastereomer 18

citrate more polar diastereomer 19

citrate more non-polar diastereomer 20

citrate more polar diastereomer 21

citrate one of 2 diastereomers 22

hemicitrate one of 2 diastereomers 23

hemicitrate one of 2 diastereomers 24

hemicitrate more non-polar diastereomer 25

hemicitrate more polar diastereomer 26

hemicitrate one of 2 diastereomers 27

citrate one of 2 diastereomers 28

hemicitrate one of 2 diastereomers 29

citrate more polar diastereomer 30

citrate more polar diastereomer 31

citrate more polar diastereomer 32

citrate more non-polar diastereomer rotamers 33

citrate one of 2 diastereomers 34

dihydrochloride mixture of the diastereomers 35

hemicitrate one of 2 diastereomers 36

hemicitrate more non-polar diastereomer 37

citrate more polar diastereomer 38

citrate one of 2 diastereomers 39

methanesulfonate one of 2 diastereomers 40

methanesulfonate one of 2 diastereomers 41

citrate 42

citrate one of 2 diastereomers 43

citrate mixture of the diastereomers 44

hemicitrate one of 2 diastereomers 45

citrate one of 2 diastereomers 46

citrate 70:30 more non- polar:more polar diastereomer 47

citrate 30:70 more non- polar:more polar diastereomer 48

base 49

hemicitrate one of 2 diastereomers 50

methanesulfonate one of 2 diastereomers 51

citrate one of 2 diastereomers 52

citrate one of 2 diastereomers 53

base 15:85 more non- polar:more polar diastereomerInvestigations of the Activity of the Compounds According to theInvention:

The data recorded in the following assays and models are summarized inTable 1.

Measurement of the ORL1 Binding

The cyclohexane derivatives of the general formula I were investigatedin a receptor binding assay with ³H-nociceptin/orphanin FQ withmembranes from recombinant CHO-ORL1 cells. This test system wasconducted in accordance with the method described by Ardati et al. (Mol.Pharmacol., 51, 1997, p. 816-824). The concentration of³H-nociceptin/orphanin FQ in these experiments was 0.5 nM. The bindingassays were carried out with in each case 20 μg of membrane protein per200 μl batch in 50 mM hepes, pH 7.4, 10 mM MgCl₂ and 1 mM EDTA. Thebinding to the ORL1 receptor was determined using in each case 1 mgWGA-SPA beads (Amersham-Pharmacia, Freiburg) by incubation of the batchfor one hour at room temperature and subsequent measurement in a Triluxscintillation counter (Wallac, Finland). The affinity is stated in Table1 as the nanomolar K_(i) value in or % inhibition at c=1 μM.

Measurement of the μ Binding

The receptor affinity for the human μ-opiate receptor was determined ina homogeneous batch in microtitre plates. For this, dilution series ofthe particular spirocyclic cyclohexane derivative to be tested wereincubated in a total volume of 250 μl it for 90 minutes at roomtemperature with a receptor membrane preparation (15-40 μg protein per250 μl incubation batch) of CHO-K1 cells, which express the humanμ-opiate receptor (RB-HOM receptor membrane preparation of NEN,Zaventem, Belgium), in the presence of 1 nmol/l of the radioactiveligand [³H]-naloxone (NET719, NEN, Zaventem, Belgium) and of 1 mgWGA-SPA beads (wheat germ agglutinin SPA beads from Amersham/Pharmacia,Freiburg, Germany). 50 mmoles/l Tris-HCl supplemented with 0.05 wt. %sodium azide and with 0.06 wt. % bovine serum albumin was used as theincubation buffer. 25 μmoles/l naloxone was additionally added fordetermination of the non-specific binding. When the ninety minutes ofincubation time had ended, the microtitre plates were centrifuged off at1,000 g for 20 minutes and the radioactivity was measured in a β-counter(Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). Thepercentage displacement of the radioactive ligand from its binding tothe human μ-opiate receptor at a concentration of the test substances of1 μmole/l was determined and was stated as the percentage inhibition (%inhibition) of the specific binding. In some cases, on the basis of thepercentage displacement by different concentrations of the compounds ofthe general formula I to be tested, IC₅₀ inhibitory concentrations whichcause 50 percent displacement of the radioactive ligand were calculated.By conversion by means of the Cheng-Prusoff relationship, Ki values wereobtained for the test substances.

Testing for Analgesia in the Writing Test in Mice

The analgesic activity was investigated using the phenylquinone-inducedwrithing test in mice (modified in accordance with I. C. Hendershot andJ. Forsaith (1959) J. Pharmacol. Exp. Ther. 125, 237-240). Male NMRImice weighing 25 to 30 g were used for this. Groups of 10 animals persubstance dose received 0.3 ml/mouse of a 0.02% strength aqueoussolution of phenylquinone (phenylbenzoquinone, Sigma, Deisenhofen;preparation of the solution with the addition of 5% ethanol and storagein a water-bath at 45° C.) administered intraperitoneally 10 minutesafter intravenous administration of the test substances. The animalswere placed individually in observation cages. The number ofpain-induced stretching movements (so-called writhing reactions, i.e.straightening of the body with stretching of the rear extremities) wascounted by means of a push-button counter 5 to 20 minutes after theadministration of phenylquinone. Animals which receive onlyphysiological saline solution were also run as a control. All thesubstances were tested in the standard dosage of 10 mg/kg. Thepercentage inhibition (% inhibition) of the writhing reaction by asubstance was calculated according to the following formula:

${\%\mspace{14mu}{inhibition}} = {100 - {\frac{\begin{matrix}{{writhing}\mspace{14mu}{reactions}} \\{{of}\mspace{14mu}{the}\mspace{14mu}{treated}\mspace{14mu}{animals}}\end{matrix}}{\begin{matrix}{{writhing}\mspace{14mu}{reactions}} \\{{of}\mspace{14mu}{the}\mspace{14mu}{control}\mspace{14mu}{animals}}\end{matrix}}*100}}$For some substances, the ED₅₀ values with the 95% confidence range ofthe writhing reaction was calculated by means of regression analysis(evaluation program Martens EDV Service, Eckental) from thedose-dependent decrease in the writhing reactions compared withphenylquinone control groups investigated in parallel.Testing for Analgesia in the Tail Flick Test in Mice

The mice were each placed individually in a test cage and the base ofthe tail was exposed to the focused heat ray of an electric lamp (tailflick model 50/08/1.bc, Labtec, Dr. Hess). The lamp intensity wasadjusted such that the time from switching on of the lamp to suddenpulling away of the tail (pain latency) in untreated mice was 3 to 5sec. Before administration of the solutions containing the compoundaccording to the invention or the particular comparison solutions, themice were pretested twice within five minutes and the mean of thesemeasurements was calculated as the pretest mean.

The solutions of the compound of the general formula I according to theinvention and the comparison solutions were then administratedintravenously. The pain measurement was performed in each case 10, 20,40 and 60 minutes after the intravenous administration. The analgesicaction was determined as the increase in the pain latency (% of themaximum possible antinociceptive effect) according to the followingequation:[(T ₁ −T ₀)/(T ₂ −T ₀)]×100In this equation, the time T₀ is the latency time before theadministration, the time T₁ is the latency time after the administrationof the active compound combination and the time T₂ is the maximumduration of exposure (12 seconds).

TABLE 1 ORL1 μ Writhing Tail flick Ki [nM] Ki [nM] (mouse, i.v.) (mouse,i.v.) or or ED₅₀ [mg/kg] ED₅₀ [mg/kg] Example % inhibition % inhibitionor % inhibition or % inhibition No. [1 μM] [1 μM] (dose [mg/kg]) (dose[mg/kg]) 1 0.3 0.6 0.0035 2 310 3 0.6 1.3 0.0182 (i.p.) 4 3.7 3.1 6 53%7 76% 8 80% 89% (10) 9 0.26 0.36  94% (1) 10 3.4 4.5 11 2.9 4.4 12 2.42.2   67% (0.1) 13 5.8 2.0 0.0033 0.02 14 1.2 12.0 0.029 15 42.0 58.0 1623.0 14.0 17 70.0 6.6 18 29.0 25.0 19 91% 95% 20 56% 75% 21 75% 22 3.27.2   100% (0.1) 23 1.2 2.1 0.018 24 2.9 1.5 0.019 25 22.0 12.0 100% (1)26 4.5 2.7 0.039 28 1.4 1.2 0.042 29 32.0 15.0 30 58% 99% 31 6.9 17.0 321.1 1.7   100% (0.1) 33 0.5 0.5 100% (1) 34 1.4 0.7  89% (1) 35 83.061.0 36 4.4 14.0 100% (1) 37 56% 90% 38 43% 39 90% 40 55% 100%  42 75%86% 43 91% 96% 44 52.0 19.0 45 1.6 1.1 0.013 46 0.9 2.3 47 99% 2.7 4910.0 6.8 0.22 52 62.0 58.0 53 1.1 0.6

Example 54 Parenteral Solution of a Spirocyclic Cyclohexane DerivativeAccording to the Invention

38 g of one of the spirocyclic cyclohexane derivatives according to theinvention, here Example 3, are dissolved in 1 l of water for injectionpurposes at room temperature and the solution is then adjusted toisotonic conditions by addition of anhydrous glucose for injectionpurposes.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

1. A spirocyclic cyclohexane compound selected from the group consisting of: 1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorene; 1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorene; 1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-3,4-dihydro-1H-2-oxa-9-thiafluorene; 1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dioxafluorene; 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methoxy-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole; 6-bromo-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-6-nitro-1,3,4,9-tetrahydropyrano[3,4-b]indole; 6-chloro-1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole; 3,9-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-methylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-3-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole; 3,6-dimethyl-1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-3-methyl-9-phenyl-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorene; 1,1-(3-dimethylamino-3-(3-fluorophenyl)pentamethylene)-1,3,4,9-tetrahydro-2-thia-9-azafluorene; 1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-9-oxa-2-thiafluorene; 6,6-(3-dimethylamino-3-phenylpentamethylene)-1,2,3,4,4a,6,7,11c-octahydro-5-oxa-7-azabenzo[c]fluorene; 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-bromo-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-phenylpentamethylene)-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-6-ol; 1,1-(3-methylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole; 1,1-(3-dimethylamino-3-(4-fluorophenyl)pentamethylene)-3,4-dihydro-1H-2,9-dithiafluorene; 1,1-(3-dimethylamino-3-phenylpentamethylene)-3,4-dihydro-1H-2,9-dithiafluorene, and 1,1-(3-dimethylamino-3-phenylpentamethylene)-2-oxo-1,3,4,9-tetrahydro-2-thia-9-aza-fluorene, or a salt of any of the foregoing with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, methane sulfonic acid, and trifluoromethane sulfonic acid.
 2. A compound as claimed in claim 1, wherein said compound is the more polar diastereomer.
 3. A compound as claimed in claim 1, wherein said compound is the more non-polar diastereomer.
 4. A spirocyclic cyclohexane compound corresponding to a formula selected from the group consisting of:

or a salt of any of the foregoing with a physiologically acceptable acid.
 5. A compound as claimed in claim 4, wherein said compound is the more polar diastereomer.
 6. A compound as claimed in claim 4, wherein said compound is the more non-polar diastereomer.
 7. 1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole or a salt thereof with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, methane sulfonic acid, and trifluoromethane sulfonic acid.
 8. A compound as claimed in claim 7, wherein said compound is the more polar diastereomer.
 9. A compound as claimed in claim 7, wherein said compound is the more non-polar diastereomer.
 10. A spirocyclic cyclohexane compound corresponding to the formula:

or a salt thereof with a physiologically acceptable acid.
 11. A compound as claimed in claim 10, wherein said compound is the more polar diastereomer.
 12. A compound as claimed in claim 10, wherein said compound is the more non-polar diastereomer.
 13. 1,1-(3-methylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole or a salt thereof with a physiologically acceptable acid selected from the group consisting of hydrochloric acid, citric acid, tartaric acid, methane sulfonic acid, and trifluoromethane sulfonic acid.
 14. A compound as claimed in claim 13, wherein said compound is the more polar diastereomer.
 15. A compound as claimed in claim 13, wherein said compound is the more non-polar diastereomer.
 16. A spirocyclic cyclohexane compound corresponding to the formula:

or a salt thereof with a physiologically acceptable acid.
 17. A compound as claimed in claim 16, wherein said compound is the more polar diastereomer.
 18. A compound as claimed in claim 16, wherein said compound is the more non-polar diastereomer. 